tbuckley/cabot-search huggingface dataset:
Interleukin-17–Dependent Autoimmunity to Collagen Type V in Atherosclerosis
Authors: Melanie L. Dart, Ewa Jankowska-Gan, Guorui Huang, Drew A. Roenneburg, Melissa R. Keller, Jose R. Torrealba, Aaron Rhoads, Byoungjae Kim, Joseph L. Bobadilla, Lynn D. Haynes, David S. Wilkes, William J. Burlingham, Daniel S. Greenspan
Journal: Circulation Research (2010)

Rationale: Considerable evidence shows atherosclerosis to be a chronic inflammatory disease in which immunity to self-antigens contributes to disease progression. We recently identified the collagen type V [col(V)] α1(V) chain as a key autoantigen driving the Th17-dependent cellular immunity underlying another chronic inflammatory disease, obliterative bronchiolitis. Because specific induction of α1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis. Objective: To determine whether col(V) autoimmunity may be involved in the pathogenesis of atherosclerosis. Methods and Results: Here, we demonstrate Th17-dependent anti-col(V) immunity to be characteristic of atherosclerosis in human coronary artery disease (CAD) patients and in apolipoprotein E–null (ApoE −/− ) atherosclerotic mice. Responses were α1(V)-specific in CAD with variable Th1 pathway involvement. In early atherosclerosis in ApoE −/− mice, anti-col(V) immunity was tempered by an interleukin (IL)-10–dependent mechanism. In support of a causal role for col(V) autoimmunity in the pathogenesis of atherosclerosis, col(V) sensitization of ApoE −/− mice on a regular chow diet overcame IL-10–mediated inhibition of col(V) autoimmunity, leading to increased atherosclerotic burden in these mice and local accumulation of IL-17–producing cells, particularly in the col(V)-rich adventitia subjacent to the atheromas. Conclusions: These findings establish col(V) as an autoantigen in human CAD and show col(V) autoimmunity to be a consistent feature in atherosclerosis in humans and mice. Furthermore, data are consistent with a causative role for col(V) in the pathogenesis of atherosclerosis.
Multiple Cerebral Infarctions and Intracranial Vessel Abnormalities
Authors: Eline A. Oudeman, Catharina J. M. Frijns, Catharina J. M. Klijn
Journal: JAMA (2013)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Familial Risk of Cancer Shortly After Diagnosis of the First Familial Tumor
Authors: J. Lorenzo Bermejo, Kari Hemminki
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: The diagnosis of the first cancer in a family may lead to the medical examination of the patient's relatives and the subsequent identification of additional familial cancers. If detection bias is present, familial risks could be overestimated soon after first diagnosis. Methods: We followed 1 677 722 offspring/siblings of 846 448 probands from the year of diagnosis of the first familial tumor to the diagnosis of first cancer, death, emigration, or December 31, 2002, using the Swedish Family Cancer Database. The risks of cancer among the offspring and siblings of patients with melanoma and cancers of the breast, prostate, colorectum, cervix, and lung were compared with those in the general population. Relative risks (RRs) were determined using Poisson regression, according to the time after first diagnosis. All statistical tests were two-sided. Results: Daughters of women with breast cancer had a statistically significantly higher relative risk of in situ breast cancer during the year of the mother's diagnosis than they did 5 or more years later (RR = 4.78, 95% confidence interval [CI] = 2.16 to 10.6, 26.6 cases per 100 000, versus RR = 1.97, 95% CI = 1.65 to 2.37, 27.2 cases per 100 000; P = .033). Daughters diagnosed the same year as their mothers were younger and were diagnosed earlier in the calendar year than daughters of women diagnosed 5 or more years after their mothers. Similarly, the risk of invasive melanoma among the offspring of individuals with invasive melanoma was higher during the year of the parent's diagnosis than it was 5 or more years afterward (RR = 8.27, 95% CI = 3.82 to 17.9, 57.0 cases per 100 000, versus RR = 3.18, 95% CI = 2.55 to 3.97, 37.6 cases per 100 000; P = .019). Sibling risks of in situ breast cancer, in situ cervical cancer, and invasive prostate cancer also decreased with time after diagnosis of the first familial tumor. Conclusions: Increased surveillance may result in the earlier detection of asymptomatic familial cancers, i.e., in detection bias. The possibility of overestimated familial risks of cancer shortly after diagnosis of the first familial tumor should be considered before a patient's clinical and genetic counseling is implemented.
Mitogen-Activated Protein Kinase Phosphatase-1 in Human Breast Cancer Independently Predicts Prognosis and Is Repressed by Doxorubicin
Authors: Federico Rojo, Irene González-Navarrete, Rafael Bragado, Alba Dalmases, Silvia Menéndez, Maria Cortes-Sempere, Cristina Suárez, Cristina Oliva, Sonia Servitja, Vanesa Rodriguez-Fanjul, Isabel Sánchez-Pérez, Clara Campas, Josep Maria Corominas, Ignasi Tusquets, Beatriz Bellosillo, Sergi Serrano, Rosario Perona, Ana Rovira, Joan Albanell
Journal: Clinical Cancer Research (2009)

Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) dephosphorylates mitogen-activated protein kinase [extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38], mediates breast cancer chemoresistance, and is repressible by doxorubicin in breast cancer cells. We aimed to characterize doxorubicin effects on MKP-1 and phospho-MAPKs in human breast cancers and to further study the clinical relevance of MKP-1 expression in this disease.Doxorubicin effects on MKP-1, phospho-ERK1/2 (p-ERK1/2), phospho-JNK (p-JNK), and phospho-p38 were assayed in a panel of human breast cancer cells by Western blot and in human breast cancer were assayed ex vivo by immunohistochemistry (n = 50). MKP-1 expression was also assayed in a range of normal to malignant breast lesions (n = 30) and in a series of patients (n = 96) with breast cancer and clinical follow-up.MKP-1 was expressed at low levels in normal breast and in usual ductal hyperplasia and at high levels in in situ carcinoma. MKP-1 was overexpressed in approximately 50% of infiltrating breast carcinomas. Similar to what was observed in breast cancer cell lines, ex vivo exposure of breast tumors to doxorubicin down-regulated MKP-1, and up-regulated p-ERK1/2 and p-JNK, in the majority of cases. However, in a proportion of tumors overexpressing MKP-1, doxorubicin did not significantly affect MKP-1 or phospho-MAPKs. With regard to patient outcome, MKP-1 overexpression was an adverse prognostic factor for relapse both by univariate (P < 0.001) and multivariate analysis (P = 0.002).MKP-1 is overexpressed during the malignant transformation of the breast and independently predicts poor prognosis. Furthermore, MKP-1 is repressed by doxorubicin in many human breast cancers.
From small studies to precision medicine: prioritizing candidate biomarkers
Authors: Daniel P Gaile, Jeffrey C Miecznikowski
Journal: Genome Medicine (2013)

There are still many open questions in data-analytic research pertaining to biomarker development in the era of personalized/precision medicine and big data. Among them is the question of what constitutes best practice for the extraction of prioritized lists of candidate biomarkers from smaller studies that are 'hypothesis generating' in nature. A recent comparison of methods to detect patient-specific aberrant expression events in small- to medium-sized (10 to 50 samples) studies provides results that favor the use of outlying degree methods. See related Research, http://genomemedicine.com/content/5/11/103.
Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma
Authors: Alexander Stoeck, Serguei Lejnine, Andrew Truong, Li Pan, Hongfang Wang, Chongzhi Zang, Jing Yuan, Chris Ware, John MacLean, Philip W. Garrett-Engele, Michael Kluk, Jason Laskey, Brian B. Haines, Christopher Moskaluk, Leigh Zawel, Stephen Fawell, Gary Gilliland, Theresa Zhang, Brandon E. Kremer, Birgit Knoechel, Bradley E. Bernstein, Warren S. Pear, X. Shirley Liu, Jon C. Aster, Sriram Sathyanarayanan
Journal: Cancer Discovery (2014)

Abstract Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD–low tumors without NOTCH1 mutations were resistant. Significance: NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies. Cancer Discov; 4(10); 1154–67. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 1103
Preparing for sudden cardiac arrest—the essential role of automated external defibrillators in athletic medicine: a critical review
Authors: J A Drezner
Journal: British Journal of Sports Medicine (2009)

Sudden cardiac arrest (SCA) is the leading cause of death in exercising young athletes. Three factors—prompt recognition of SCA, the presence of a trained rescuer to initiate cardiopulmonary resuscitation (CPR) and access to early defibrillation through on-site automated external defibrillators (AEDs)—are critical to improving survival. Schools, clubs and organisations sponsoring athletic events should have an established emergency response plan for SCA. Essential elements of an emergency response plan include an effective communication system to alert first responders and retrieve the AED, training of anticipated responders in CPR and AED use, access to an AED for early defibrillation, integration of on-site AED programmes with the local emergency medical services system, and practice and review of the response plan. Timely access to AEDs at training and sporting competitions permits effective management of SCA and the prevention of sudden cardiac death in athletes. SCA should be suspected in any collapsed and unresponsive athlete and an AED applied as soon as possible for rhythm analysis and defibrillation if indicated. This article reviews emergency response planning for SCA and highlights recent data that provide a compelling case for the essential role of AEDs in the athletic setting.
Exon-Intron Structure and Evolution of the Lipocalin Gene Family
Authors: D. Sanchez
Journal: Molecular Biology and Evolution (2003)

The Lipocalins are an ancient protein family whose expression is currently confirmed in bacteria, protoctists, plants, arthropods, and chordates. The evolution of this protein family has been assessed previously using amino acid sequence phylogenies. In this report we use an independent set of characters derived from the gene structure (exon-intron arrangement) to infer a new lipocalin phylogeny. We also present the novel gene structure of three insect lipocalins. The position and phase of introns are well preserved among lipocalin clades when mapped onto a protein sequence alignment, suggesting the homologous nature of these introns. Because of this homology, we use the intron position and phase of 23 lipocalin genes to reconstruct a phylogeny by maximum parsimony and distance methods. These phylogenies are very similar to the phylogenies derived from protein sequence. This result is confirmed by congruence analysis, and a consensus tree shows the commonalities between the two source trees. Interestingly, the intron arrangement phylogeny shows that metazoan lipocalins have more introns than other eukaryotic lipocalins, and that intron gains have occurred in the C-termini of chordate lipocalins. We also analyze the relationship of intron arrangement and protein tertiary structure, as well as the relationship of lipocalins with members of the proposed structural superfamily of calycins. Our congruence analysis validates the gene structure data as a source of phylogenetic information and helps to further refine our hypothesis on the evolutionary history of lipocalins.
The phosphoinositide 3-kinase inhibitor LY294002 enhances cardiac myocyte contractility via a direct inhibition of Ik,slow currents
Authors: H SUN
Journal: Cardiovascular Research (2004)

Phosphoinositide 3-kinase (PI3K) is a key component in regulating myocardial growth, survival and contractility. LY294002 and wortmannin are two PI3K inhibitors used widely to establish the role of PI3K. The goal of this study was to examine the effects of acute application of LY294002 and wortmannin on cardiac myocyte contractility and underlying mechanisms.Patch-clamp, indo-1 epifluorescence and video-edge detection techniques were used to measure outward K(+) currents, action potentials (AP), Ca(2+) transients and shortening of myocytes isolated from mouse left ventricular free wall.In field-stimulated myocytes, LY294002 (10 micromol/l) increased Ca(2+) transient amplitude by 23%, and cell shortening amplitude by 60% in the absence or presence of wortmannin, while wortmannin alone had no effect. LY294002 (but not wortmannin) prolonged AP duration by specifically inhibiting slowly inactivating K(+) currents (i.e., the 4-aminopyrydine-sensitive I(k,slow1) and the tetraethylammonium-sensitive I(k,slow2)), leading to an increase in sarcoplasmic reticular Ca(2+) levels. It appeared that the AP prolongation was responsible for elevated contractility since AP-clamp of myocytes with prolonged APs (recorded in LY294002-treated myocytes) induced a 29% increase in cell shortening compared with control APs, while LY294002 application did not increase contractility in voltage-clamp studies using either step or AP depolarizations.The putative PI3K inhibitor LY294002 increases Ca(2+) release and myocyte contractility via direct inhibition of cardiac I(k,slow) and AP prolongation, thus limiting the usefulness of this agent in the analyses of the role of PI3K in heart function.
Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H).
Authors: A E Gharavi, L R Sammaritano, J Wen, K B Elkon
Journal: Journal of Clinical Investigation (1992)

A subset of patients with systemic lupus erythematosus has autoantibodies to acidic phospholipids. Since lipids are poor immunogens, the mechanism responsible for the induction of these antibodies is unclear. Immunization of a normal rabbit and normal mice with purified human beta 2-glycoprotein I (apolipoprotein H) resulted in the production of high levels of two non-cross-reactive antibody populations, anti-apolipoprotein H, and antiphospholipid. The antiphospholipid antibodies had binding specificities indistinguishable from autoantibodies obtained from human and murine lupus. These findings suggest a novel mechanism for the induction of antiphospholipid autoantibodies.
Jewish Law and Time of Death
Authors: Rabbi Aaron Soloveichik
Journal: JAMA (1978)

<h3>To the Editor.—</h3> The article dealing with brain death (238:1651, 1977) contains a serious misinterpretation of Jewish law pertaining to establishment of the time of death. The statement that "absent heartbeat or pulse was<i>not</i>considered a significant factor in ascertaining death in any early religious sources" is a manifest error. In fact, the source to which the reader is directed by the footnote, Babylonian Talmud Tractate Yoma 85A, serves to establish precisely the opposite position. Jewish law recognizes the presence of any vital function, including heart action, as indicative of at least residual life. Termination of such life by means of "pulling the plug" or otherwise constitutes an act of homicide. Moreover, a sharp distinction must be drawn between partial and total destruction of the brain. The authors state that the Harvard criteria signify that "when the criteria have been fulfilled, there is widespread destruction of the brain" and
Prevention of hyperoxia-mediated pulmonary inflammation in neonatal rats by caffeine
Authors: Ulrike Weichelt, Ruhuye Cay, Thomas Schmitz, Evelyn Strauss, Marco Sifringer, Christoph Bührer, Stefanie Endesfelder
Journal: European Respiratory Journal (2012)

In preterm human infants, briefly elevated concentrations of oxygen are associated with a prolonged increase in blood chemokine concentrations and the development of bronchopulmonary dysplasia (BPD). Caffeine given to preterm infants for the prevention or treatment of apnoea has been shown to reduce the rate of BPD. We tested the hypotheses that infant rats exposed to a combination of caffeine and hyperoxia would be less susceptible to lung injury than those exposed to hyperoxia alone and that caffeine decreases the pulmonary tissue expression of chemokines and leukocyte influx following hyperoxia. Using 6-day-old rat pups, we demonstrated that 24 h of 80% oxygen exposure caused pulmonary recruitment of neutrophils and macrophages. High levels of oxygen upregulated the expression of: the CXC chemokines, cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2; the CC-chemokine monocyte chemoattractant protein-1; the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6, as measured by realtime PCR after the administration of caffeine (10 mg · kg(-1) body weight); and attenuated chemokine and cytokine upregulation, as well as the influx of CD11b(+), ED-1(+) and myeloperoxidase(+) leukocytes. These experiments suggest that protective effects of caffeine in the neonatal lung are mediated, at least in part, by reduction of pulmonary inflammation.
L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure
Authors: Lars Marius Ytreb, Rune Gangsy Kristiansen, Hanne Mæhre, Ole Martin Fuskevåg, Trine Kalstad, Arthur Revhaug, María Jover Cobos, Rajiv Jalan, Christopher F. Rose
Journal: Hepatology (2009)

Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a combination of L-ornithine and phenylacetate (OP) would synergistically reduce toxic levels of ammonia by (1) L-ornithine increasing glutamine production (ammonia removal) through muscle glutamine synthetase and (2) phenylacetate conjugating with the ornithine-derived glutamine to form phenylacetylglutamine, which is excreted into the urine. The aims of this study were to determine the effect of OP on arterial and extracellular brain ammonia concentrations as well as ICP in pigs with ALF (induced by liver devascularization). ALF pigs were treated with OP (L-ornithine 0.07 g/kg/hour intravenously; phenylbutyrate, prodrug for phenylacetate; 0.05 g/kg/hour intraduodenally) for 8 hours following ALF induction. ICP was monitored throughout, and arterial and extracellular brain ammonia were measured along with phenylacetylglutamine in the urine. Compared with ALF + saline pigs, treatment with OP significantly attenuated concentrations of arterial ammonia (589.6 +/- 56.7 versus 365.2 +/- 60.4 mumol/L [mean +/- SEM], P= 0.002) and extracellular brain ammonia (P= 0.01). The ALF-induced increase in ICP was prevented in ALF + OP-treated pigs (18.3 +/- 1.3 mmHg in ALF + saline versus 10.3 +/- 1.1 mmHg in ALF + OP-treated pigs;P= 0.001). The value of ICP significantly correlated with the concentration of extracellular brain ammonia (r(2) = 0.36,P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 +/- 0.6 micromol/L in ALF + OP-treated pigs versus 0.5 +/- 0.04 micromol/L in ALF + saline-treated pigs (P< 0.001).L-Ornithine and phenylacetate act synergistically to successfully attenuate increases in arterial ammonia, which is accompanied by a significant decrease in extracellular brain ammonia and prevention of intracranial hypertension in pigs with ALF.
Failure of Immunity Responses in Localized Disease
Authors: W. H. Hughes
Journal: BMJ (1945)

~~~~~~~~~~~~~~~~~~~~~~~~MEDICAL JOURNAL from the relative positions of the distended cervix and the site of the obliterated os externum.In most cases of acquired haematometra the stenosis is in- complete and there, is some leakage past the obstruction.So complete an obstruction and so extensive a haematometra as that here described must be very rare.
Tension pneumothorax mimicking giant emphysematous bullae
Authors: M. Gonzalez, T. Krueger, H.-B. Ris, J. Y. Perentes
Journal: Thorax (2010)

A 65-year-old man was admitted with left thoracic pain and dyspnoea. One year before admission, he had undergone talc pleurodesis by thoracoscopy to manage a left recurrent pneumothorax due to tobacco-related emphysema. Chest x-ray (figure 1) and CT scan (figure 2A–C) showed clustered air pockets in between normal lung parenchyma. It was unclear whether the radiological image was due to unilateral giant emphysematous bullae or to clustered pneumothorax following talcage, with areas of lung detachment in between areas of lung adhesion …