tbuckley/cabot-search huggingface dataset:
An Interstitial Deletion at 3p21.3 Results in the Genetic Fusion of<i>MLH1</i>and<i>ITGA9</i>in a Lynch Syndrome Family
Authors: Claus Meyer, Angela Brieger, Guido Plotz, Nicole Weber, Sandra Passmann, Theo Dingermann, Stefan Zeuzem, Joerg Trojan, Rolf Marschalek
Journal: Clinical Cancer Research (2009)

Germline mutations in DNA mismatch repair genes, mainly MLH1 or MSH2, have been shown to predispose with high penetrance for the development of the clinical phenotype of hereditary nonpolyposis colorectal cancer (Lynch syndrome). Here, we describe the discovery and first functional characterization of a novel germline MLH1 mutant allele.A large kindred including 54 potential carriers was investigated at the molecular level by using different types of PCR experiments, gene cloning, transfection studies, Western blot experiments, and mismatch repair assays to identify and characterize a novel MLH1 mutant allele. Twenty-two of 54 putative carriers developed colon cancer or other tumors, including breast cancer.The identified MLH1 mutant allele emerged from an interstitial deletion on chromosome 3p21.3, leading to an in-frame fusion of MLH1 (exons 1-11) with ITGA9 (integrin alpha 9; exons 17-28). The deleted area has a size of about 400 kb; codes for LRRFIP2 (leucine-rich repeat in flightless interaction protein 2), GOLGA4 (Golgi autoantigen, golgin subfamily a, 4), and C3orf35/APRG1 (chromosome 3 open reading frame 35/AP20 region protein 1); and partly disrupts the AP20 region implicated in major epithelial malignancies. Tumor cells lost their second MLH1 allele. The MLH1*ITGA9 fusion protein provides no capability for DNA mismatch repair. Murine fibroblasts, expressing a doxycycline-inducible MLH1*ITGA9 fusion gene, exhibit a loss-of-contact inhibition phenotype.This is the first description of a functional gene fusion of the human MLH1 gene, resulting in the loss of mismatch repair capabilities. The MLH1*ITGA9 fusion allele, together with deletions of the AP20 region, presumably defines a novel subclass of Lynch syndrome patients, which results in an extended tumor spectrum known from hereditary nonpolyposis colorectal cancer and Muir-Torre syndrome patients.
Beneficial effects of fumarate therapy in psoriasis vulgaris patients coincide with downregulation of type 1 cytokines
Authors: N.H.R. Litjens, P.H. Nibbering, A.J. Barrois, T.P.L. Zomerdijk, A.C. Van Den Oudenrijn, K.C. Noz, M. Rademaker, P.H. Van De Meide, J.T. Van Dissel, B. Thio
Journal: British Journal of Dermatology (2003)

Journal Article Beneficial effects of fumarate therapy in psoriasis vulgaris patients coincide with downregulation of type 1 cytokines Get access N.H.R. Litjens, N.H.R. Litjens Department of Infectious Diseases, C5‐P, Leiden University Medical Center, 2300 RC Leiden, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar P.H. Nibbering, P.H. Nibbering Department of Infectious Diseases, C5‐P, Leiden University Medical Center, 2300 RC Leiden, the Netherlands P.H.Nibbering. E‐mail: p.h.nibbering@lumc.nl Search for other works by this author on: Oxford Academic Google Scholar A.J. Barrois, A.J. Barrois Department of Infectious Diseases, C5‐P, Leiden University Medical Center, 2300 RC Leiden, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar T.P.L. Zomerdijk, T.P.L. Zomerdijk Department of Infectious Diseases, C5‐P, Leiden University Medical Center, 2300 RC Leiden, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar A.C. Van Den Oudenrijn, A.C. Van Den Oudenrijn Department of Infectious Diseases, C5‐P, Leiden University Medical Center, 2300 RC Leiden, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar K.C. Noz, K.C. Noz Department of Dermatology, Leyenburg Hospital, The Hague, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar M. Rademaker, M. Rademaker Department of Infectious Diseases, C5‐P, Leiden University Medical Center, 2300 RC Leiden, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar P.H. Van De Meide, P.H. Van De Meide U‐CyTech, University of Utrecht, Utrecht, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar J.T. Van Dissel, J.T. Van Dissel Department of Infectious Diseases, C5‐P, Leiden University Medical Center, 2300 RC Leiden, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar B. Thio B. Thio Department of Dermatology and Venereology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 148, Issue 3, 1 March 2003, Pages 444–451, https://doi.org/10.1046/j.1365-2133.2003.05153.x Published: 01 March 2003 Article history Accepted: 08 September 2002 Published: 01 March 2003
A Novel Endothelial L-Selectin Ligand Activity in Lymph Node Medulla That Is Regulated by α(1,3)-Fucosyltransferase-IV
Authors: Christine M'Rini, Guiying Cheng, Colleen Schweitzer, Lois L. Cavanagh, Roger T. Palframan, Thorsten R. Mempel, Richard A. Warnock, John B. Lowe, Elizabeth J. Quackenbush, Ulrich H. von Andrian
Journal: The Journal of Experimental Medicine (2003)

Lymphocytes home to peripheral lymph nodes (PLNs) via high endothelial venules (HEVs) in the subcortex and incrementally larger collecting venules in the medulla. HEVs express ligands for L-selectin, which mediates lymphocyte rolling. L-selectin counterreceptors in HEVs are recognized by mAb MECA-79, a surrogate marker for molecularly heterogeneous glycans termed peripheral node addressin. By contrast, we find that medullary venules express L-selectin ligands not recognized by MECA-79. Both L-selectin ligands must be fucosylated by α(1,3)-fucosyltransferase (FucT)-IV or FucT-VII as rolling is absent in FucT-IV+VII−/− mice. Intravital microscopy experiments revealed that MECA-79–reactive ligands depend primarily on FucT-VII, whereas MECA-79–independent medullary L-selectin ligands are regulated by FucT-IV. Expression levels of both enzymes paralleled these anatomical distinctions. The relative mRNA level of FucT-IV was higher in medullary venules than in HEVs, whereas FucT-VII was most prominent in HEVs and weak in medullary venules. Thus, two distinct L-selectin ligands are segmentally confined to contiguous microvascular domains in PLNs. Although MECA-79–reactive species predominate in HEVs, medullary venules express another ligand that is spatially, antigenically, and biosynthetically unique. Physiologic relevance for this novel activity in medullary microvessels is suggested by the finding that L-selectin–dependent T cell homing to PLNs was partly insensitive to MECA-79 inhibition.
Standardized Ki67 Diagnostics Using Automated Scoring—Clinical Validation in the GeparTrio Breast Cancer Study
Authors: Frederick Klauschen, Stephan Wienert, Wolfgang D. Schmitt, Sibylle Loibl, Bernd Gerber, Jens-Uwe Blohmer, Jens Huober, Thomas Rüdiger, Erhard Erbstößer, Keyur Mehta, Bianca Lederer, Manfred Dietel, Carsten Denkert, Gunter von Minckwitz
Journal: Clinical Cancer Research (2014)

Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of "visual" Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies.We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring.The three groups of autoKi67 as defined by low (≤ 15%), medium (15.1%-35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values P(OS) < 0.0001 and P(PFS) < 0.0002, compared with P(OS) < 0.0005 and P(PFS) < 0.0001 for manual Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with P(OS) = 0.002, P(PFS) = 0.009 (autoKi67) versus P(OS) = 0.007, PPFS = 0.004 (manual Ki67).The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics.
Breast Cancer Screening for Women at Average Risk
Authors: Kevin C. Oeffinger, Elizabeth T. H. Fontham, Ruth Etzioni, Abbe Herzig, James S. Michaelson, Ya-Chen Tina Shih, Louise C. Walter, Timothy R. Church, Christopher R. Flowers, Samuel J. LaMonte, Andrew M. D. Wolf, Carol DeSantis, Joannie Lortet-Tieulent, Kimberly Andrews, Deana Manassaram-Baptiste, Debbie Saslow, Robert A. Smith, Otis W. Brawley, Richard Wender
Journal: JAMA (2015)

Breast cancer is a leading cause of premature mortality among US women. Early detection has been shown to be associated with reduced breast cancer morbidity and mortality.To update the American Cancer Society (ACS) 2003 breast cancer screening guideline for women at average risk for breast cancer.The ACS commissioned a systematic evidence review of the breast cancer screening literature to inform the update and a supplemental analysis of mammography registry data to address questions related to the screening interval. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms.Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health. Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages because of the greater number of mammograms, as well as the higher recall rate in younger women. The quality of the evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence. Analysis examining the screening interval demonstrates more favorable tumor characteristics when premenopausal women are screened annually vs biennially. Evidence does not support routine clinical breast examination as a screening method for women at average risk.The ACS recommends that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years (strong recommendation). Women aged 45 to 54 years should be screened annually (qualified recommendation). Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation). Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation). Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation). The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age (qualified recommendation).These updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer screening.
Inhibition of p38 Mitogen-Activated Protein Kinase Is Effective in the Treatment of Experimental Crescentic Glomerulonephritis and Suppresses Monocyte Chemoattractant Protein-1 but Not IL-1β or IL-6
Authors: Abdulmunem Sheryanna, Gurjeet Bhangal, John McDaid, Jennifer Smith, Anthony Manning, Brian M.J. Foxwell, Marc Feldmann, H. Terence Cook, Charles D. Pusey, Frederick W.K. Tam
Journal: Journal of the American Society of Nephrology (2007)

Activation of p38 mitogen-activated protein kinase (MAPK) is known to be important in cytokine production and cell survival in inflammation. This study examined the effect of inhibiting p38 MAPK after onset of renal injury in an experimental model of crescentic glomerulonephritis. Furthermore, this study investigated whether p38 MAPK inhibition would cause widespread suppression of the cytokine network in vivo or uncontrolled apoptosis. In the in vivo studies, daily treatment with a p38 MAPKalpha/beta inhibitor was started 1 h (early treatment study) or 4 d (late treatment study) after induction of nephrotoxic nephritis in Wistar Kyoto rats. The treated rats remained healthy with normal weight gain during the study. Both early and late treatment with p38 MAPK inhibitor reduced renal monocyte chemoattractant protein-1 (MCP-1) levels, the number of glomerular macrophages, the severity of tissue injury, and proteinuria compared with the vehicle group. Unexpected, treatment with p38 MAPK inhibitor did not suppress renal levels of IL-1beta or IL-6. In the in vitro study, the p38 MAPKalpha/beta inhibitor reduced production of MCP-1 and IL-6 by TNF-alpha-or IL-1beta-stimulated mesangial cells without any effect on cell viability or apoptosis. In conclusion, p38 MAPK inhibition is effective in reducing the severity of crescentic glomerulonephritis even when treatment is started after onset of disease. The therapeutic effect is associated with selective suppression of MCP-1, without widespread suppression of cytokine production or increased apoptosis. Therefore, p38 MAPK therapeutic blockade is a promising strategy in the treatment of antibody-mediated glomerulonephritis.
The Preventable Causes of Death in the United States: Comparative Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors
Authors: Goodarz Danaei, Eric L. Ding, Dariush Mozaffarian, Ben Taylor, Jürgen Rehm, Christopher J. L. Murray, Majid Ezzati
Journal: PLoS Medicine (2009)

Knowledge of the number of deaths caused by risk factors is needed for health policy and priority setting. Our aim was to estimate the mortality effects of the following 12 modifiable dietary, lifestyle, and metabolic risk factors in the United States (US) using consistent and comparable methods: high blood glucose, low-density lipoprotein (LDL) cholesterol, and blood pressure; overweight-obesity; high dietary trans fatty acids and salt; low dietary polyunsaturated fatty acids, omega-3 fatty acids (seafood), and fruits and vegetables; physical inactivity; alcohol use; and tobacco smoking.We used data on risk factor exposures in the US population from nationally representative health surveys and disease-specific mortality statistics from the National Center for Health Statistics. We obtained the etiological effects of risk factors on disease-specific mortality, by age, from systematic reviews and meta-analyses of epidemiological studies that had adjusted (i) for major potential confounders, and (ii) where possible for regression dilution bias. We estimated the number of disease-specific deaths attributable to all non-optimal levels of each risk factor exposure, by age and sex. In 2005, tobacco smoking and high blood pressure were responsible for an estimated 467,000 (95% confidence interval [CI] 436,000-500,000) and 395,000 (372,000-414,000) deaths, accounting for about one in five or six deaths in US adults. Overweight-obesity (216,000; 188,000-237,000) and physical inactivity (191,000; 164,000-222,000) were each responsible for nearly 1 in 10 deaths. High dietary salt (102,000; 97,000-107,000), low dietary omega-3 fatty acids (84,000; 72,000-96,000), and high dietary trans fatty acids (82,000; 63,000-97,000) were the dietary risks with the largest mortality effects. Although 26,000 (23,000-40,000) deaths from ischemic heart disease, ischemic stroke, and diabetes were averted by current alcohol use, they were outweighed by 90,000 (88,000-94,000) deaths from other cardiovascular diseases, cancers, liver cirrhosis, pancreatitis, alcohol use disorders, road traffic and other injuries, and violence.Smoking and high blood pressure, which both have effective interventions, are responsible for the largest number of deaths in the US. Other dietary, lifestyle, and metabolic risk factors for chronic diseases also cause a substantial number of deaths in the US.
Long-term protein exposure reduces albumin binding and uptake in proximal tubule-derived opossum kidney cells.
Authors: M Gekle, S Mildenberger, R Freudinger, S Silbernagl
Journal: Journal of the American Society of Nephrology (1998)

To avoid renal loss of large amounts of proteins, filtered proteins are reabsorbed by endocytosis along the proximal tubule. However, although protein reabsorption is a task of proximal tubular cells, it is also a threat because it may cause cell injury. This study determines whether exposure to bovine serum albumin (BSA) leads to regulatory changes in endocytosis of FITC-BSA in proximal tubule-derived opossum kidney cells. Preincubation with BSA led to a decrease of FITC-BSA endocytosis with an IC50 value of 0.58 g/L. Specific binding of FITC-BSA to the apical membrane was also reduced (IC50 = 0.69 g/L). Kinetic analyses revealed that maximal uptake rate and maximal binding capacity were decreased with no change in affinity. Similar effects were observed after preincubation with equimolar amounts of other proteins (lactalbumin, transferrin, and conalbumin), but not after preincubation with dextran. The effect of preincubation with BSA could be mimicked by preincubation with some amino acids. Preincubation with L-Ala, L-Gln, or NH4Cl, but not with L-Leu, L-Glu, or L-Asp, reduced FITC-BSA endocytosis and binding. Preincubation with BSA, but not with dextran, reduced protein degradation and increased ammonia production, vesicular pH, as well as the rate of lactate dehydrogenase release. Apical fluid-phase endocytosis and apical uptake of neutral amino acids were not reduced. It is concluded that proximal tubular cells reduce the uptake rate for proteins, but not for other substrates, in response to increased protein load. This reduction is achieved by reducing the number of apical binding sites, partially in response to increased ammoniagenesis with deranged vesicular pH and enzyme activities. Thus, increased protein filtration could result in reduced protein reabsorption, thereby enhancing proteinuria.
Angiopoietin‐2 in acute myocardial infarction complicated by cardiogenic shock—a biomarker substudy of the <scp>IABP‐SHOCK II</scp>‐Trial
Authors: Janine Pöss, Georg Fuernau, Daniel Denks, Steffen Desch, Ingo Eitel, Suzanne de Waha, Andreas Link, Gerhard Schuler, Volker Adams, Michael Böhm, Holger Thiele
Journal: European Journal of Heart Failure (2015)
Parasite Burden and Severity of Malaria in Tanzanian Children
Authors: Bronner Gonçalves, Michal Fried, Patrick Duffy
Journal: New England Journal of Medicine (2014)

Severe Plasmodium falciparum malaria is a major cause of death in children. The contribution of the parasite burden to the pathogenesis of severe malaria has been controversial.We documented P. falciparum infection and disease in Tanzanian children followed from birth for an average of 2 years and for as long as 4 years.Of the 882 children in our study, 102 had severe malaria, but only 3 had more than two episodes. More than half of first episodes of severe malaria occurred after a second infection. Although parasite levels were higher on average when children had severe rather than mild disease, most children (67 of 102) had high-density infection (>2500 parasites per 200 white cells) with only mild symptoms before severe malaria, after severe malaria, or both. The incidence of severe malaria decreased considerably after infancy, whereas the incidence of high-density infection was similar among all age groups. Infections before and after episodes of severe malaria were associated with similar parasite densities. Nonuse of bed nets, placental malaria at the time of a woman's second or subsequent delivery, high-transmission season, and absence of the sickle cell trait increased severe-malaria risk and parasite density during infections.Resistance to severe malaria was not acquired after one or two mild infections. Although the parasite burden was higher on average during episodes of severe malaria, a high parasite burden was often insufficient to cause severe malaria even in children who later were susceptible. The diverging rates of severe disease and high-density infection after infancy, as well as the similar parasite burdens before and after severe malaria, indicate that naturally acquired resistance to severe malaria is not explained by improved control of parasite density. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Transarterial oily chemoembolization for the treatment of hepatocellular carcinoma: A multivariate analysis of prognostic factors
Authors: Luca Mondazzi, Riccardo Bottelli, Giorgio Brambilla, Antonio Rampoldi, Indira Rezakovic, Claudio Zavaglia, Alberto Alberti, Gaetano Idèo
Journal: Hepatology (1994)

A total of 84 patients with hepatocellular carcinoma and cirrhosis were analyzed retrospectively to investigate prognostic factors. All patients received transarterial oily chemoembolization as the only anticancer therapy. The follow-up range was 1 to 39 mo (median, 9.5 mo). The overall actuarial survival rates at 12, 24 and 30 mo were 62%, 31% and 24%, respectively. According to univariate analysis, variables significantly associated with survival were age, Child-Pugh grade, total serum bilirubin, Okuda stage, tumor size, degree of labeling of the tumor with Lipiodol, gelatin foam use, changes with treatment in tumor size and changes with treatment in alpha-fetoprotein concentration. Two multivariate analyses were performed. When pretreatment and treatment variables were considered, parameters with independent prognostic value were age, Child-Pugh grade, total serum bilirubin, tumor size and degree of Lipiodol labeling of the tumor. When follow-up variables were also considered, we (a) confirmed the prognostic significance of all these parameters (age, Child-Pugh grade, total serum bilirubin, tumor size) and (b) found the independent prognostic value of the change in tumor size (or change in alpha-fetoprotein concentration). Both models yielded different risk coefficients for each class of each variable. Two simple prognostic indexes, based on these coefficients, are proposed: an "initial" index (including pretreatment and treatment variables) and a "follow-up" index (also including follow-up variables). According to the two indexes, the patients were classified into three groups with different prognoses: good (93% and 100% actuarial survival at 1 yr for the initial and follow-up indexes, respectively), intermediate (65% and 53%, respectively) and poor (27% for both indexes).