tbuckley/cabot-search huggingface dataset:
Abstract IA27: Cell fate determinants as regulators of cancer metastasis
Authors: Yibin Kang
Journal: Cancer Research (2013)

Abstract An emerging class of genes dictating malignant behavior is cell fate regulators. In the orderly development of a given tissue, the balance between cellular differentiation and division/migration is precisely controlled by a number of lineage specific transcription factors to maintain normal tissue architecture. Deregulation of such cell fate determinants have been increasingly linked to cancer metastasis, and have been shown to play critical roles in regulating cancer stem cell activity, epithelial-mesenchymal transition (EMT), tumor invasion and metastatic colonization. In our study of the mammary gland development, we found that the transcription factor Elf5, a key regulator of alveologenesis in the mammary gland, also plays a critical role in regulating the stem/progenitor function of the mammary epithelium. Targeted deletion of Elf5 in the mammary glands leads to accumulation of cell types with dual luminal/basal properties such as coexpression of K8 and K14 and an increase in CD61(+) luminal progenitor population during pregnancy. Further interrogation suggests that the abnormal increase in K14(+) K8(+) cells may represent the CD61(+) luminal progenitors blocked in differentiation. Remarkably, Elf5 deficiency in mammary epithelium also triggers an increase of adult mammary stem activity as evidenced by the accumulation of mammary stem cell (MaSC)-enriched cell population in both pregnant and virgin mice and further confirmed by mammosphere and transplantation assays. In addition to controlling cell fate determination, Elf5 also inhibits EMT in both mammary gland development and metastasis. This specific role for Elf5 in suppressing EMT and metastasis was uncovered via analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary gland tumor progression, and clinical breast cancer samples. Furthermore, we demonstrate that this role of Elf5 is mediated by the direct transcriptional repression of Snail2/Slug, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish a broad molecular function of Elf5 that extends from being a key cell lineage regulator during normal mammary gland development to serving as a suppressor of EMT and metastasis in breast cancer. Citation Format: Yibin Kang. Cell fate determinants as regulators of cancer metastasis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA27.
Novel Human Vascular Endothelial Growth Factor Genes VEGF-B and VEGF-C Localize to Chromosomes 11q13 and 4q34, Respectively
Authors: Karri Paavonen, Nina Horelli-Kuitunen, Dimitri Chilov, Eola Kukk, Sari Pennanen, Olli-Pekka Kallioniemi, Katri Pajusola, Birgitta Olofsson, Ulf Eriksson, Vladimir Joukov, Aarno Palotie, Kari Alitalo
Journal: Circulation (1996)

Background Vascular endothelial growth factor (VEGF) is an important regulator of endothelial cell proliferation, migration, and permeability during embryonic vasculogenesis as well as in physiological and pathological angiogenesis. The recently isolated VEGF-B and VEGF-C cDNAs encode novel growth factor genes of the VEGF family. Methods and Results Southern blotting and polymerase chain reaction analysis of somatic cell hybrids and fluorescence in situ hybridization (FISH) of metaphase chromosomes were used to assess the chromosomal localization of VEGF-B and VEGF-C genes. The VEGF-B gene was found on chromosome 11q13, proximal to the cyclin D1 gene, which is amplified in a number of human carcinomas. However, VEGF-B was not amplified in several mammary carcinoma cell lines containing amplified cyclin D1. The VEGF-C gene was located on chromosome 4q34, close to the human aspartylglucosaminidase gene previously mapped to 4q34-35. Conclusions The VEGF-B locus in 11q13 and the VEGF-C locus in 4q34 are candidate targets for mutations that lead to vascular malformations or cardiovascular diseases.
Caregiver-infant interactions in the context of prenatal environmental health exposures in rural Costa Rica
Authors: Ameeta Dudani, Christine Till, Berna van Wendel de Joode
Journal: The Lancet Global Health (2014)

BackgroundEarly caregiving is one of the strongest influences on children's development, yet it has not been studied in the context of prenatal neurotoxin exposure. Epigenetic studies show that maternal nurturing promotes positive development in young rats who experienced prenatal environmental adversity. We explore the quality of caregiver-infant interactions in infants with prenatal pesticide exposure in banana-growing areas in rural Costa Rica.MethodsHome visits were conducted during field trips in October, 2012, and April, 2013, with a random subsample of 94 caregiver-infant dyads, living within Matina county, Limón province. Quality of caregiver-infant interaction was assessed with a standardised task of parent-child interaction (Nursing Child Assessment Satellite Training [NCAST]), which was piloted in the study population before its use. Interactions were videotaped and coded by two trained raters. Results were compared with the NCAST normative sample of US-Hispanic mothers.FindingsPrimary caregivers were on average 27·9 years of age (SD 10·2) and 88% of the caregivers were biological mothers. The mean age of children at time of assessment was 21·2 months (SD 3·5) and 60% were male. Compared with US-Hispanic mothers, 35% of our sample showed overall interaction scores at or below the 10th percentile cut-off score, indicating less than optimum interactions.InterpretationThis description of caregiving behaviours in a high-risk sample of infants with prenatal pesticide exposure, along with ongoing analyses examining associations between caregiving and infant neurodevelopmental outcomes, have important implications for early intervention work with this population and with other populations having environmental and concomitant risks.FundingYork University and the Lillian Wright Foundation.
Distribution of <i>Chlamydia pneumoniae</i> in the Human Arterial System and Its Relation to the Local Amount of Atherosclerosis Within the Individual
Authors: Aryan Vink, Marieke Poppen, Arjan H. Schoneveld, Paul J. M. Roholl, Dominique P. V. de Kleijn, Cornelius Borst, Gerard Pasterkamp
Journal: Circulation (2001)

Background — Chlamydia pneumoniae has been suggested to play a role in the origin of atherosclerosis. We studied the prevalence of C pneumoniae at multiple locations in the arterial system within the same individual. Studying the association between atherosclerosis and C pneumoniae within the individual excludes confounding by interindividual variability. Methods and Results —Postmortem, the presence in the intima/plaque and media of C pneumoniae membrane protein was determined by use of a C pneumoniae –specific monoclonal antibody. In 24 individuals, 33 arterial locations were studied (n=738 segments). Area stenosis was determined in adjacent cross sections. In all individuals, immunostaining of C pneumoniae was observed in ≥1 artery. The highest prevalences were observed in the abdominal aorta (67%), internal and common iliac arteries (41%), and coronary arteries (33%). The lowest prevalences were observed in the radial (0%) and cerebral (2%) arteries. Within the individual, area stenosis was larger in cross sections with immunoreactivity compared with cross sections without immunoreactivity (31.0±11.9% versus 14.3±6.1%, respectively; P &lt;0.001). In the individual, immunoreactivity was observed in 15±10% of the arteries (range, 3% to 45%). Between individuals, the percentage of arteries with immunoreactivity to C pneumoniae was associated with the average area stenosis throughout the arterial system ( r 2 =0.56, P &lt;0.001). Conclusions — C pneumoniae was mostly observed at locations that are related to clinically relevant features. Within the individual, the distribution of C pneumoniae is associated with the distribution of atherosclerosis. The role of the microorganism in atherosclerotic disease remains to be elucidated.
Transforming Growth Factor β Induces Apoptosis through Repressing the Phosphoinositide 3-Kinase/AKT/Survivin Pathway in Colon Cancer Cells
Authors: Jing Wang, Limin Yang, Junhua Yang, Karen Kuropatwinski, Wang Wang, Xiao-Qiong Liu, Jennie Hauser, Michael G. Brattain
Journal: Cancer Research (2008)

Abstract FET cells, derived from an early-stage colon carcinoma, are nontumorigenic in athymic mice. Stable transfection of a dominant-negative transforming growth factor β (TGFβ) type II receptor (DNRII) into FET cells that express autocrine TGFβ shows loss of TGFβ signaling and increased tumorigenicity in vivo indicating tumor suppressor activity of TGFβ signaling in this model. The ability of tumorigenic cells to withstand growth factor and nutrient deprivation stress (GFDS) is widely regarded as a key attribute for tumor formation and progression. We hypothesized that increased tumorigenicity of FET/DNRII cells was due to loss of participation of autocrine TGFβ in a “fail-safe” mechanism to generate cell death in response to this stress. Here, we document that loss of autocrine TGFβ in FET/DNRII cells resulted in greater endogenous cell survival in response to GFDS due to activation of the phosphoinositide 3-kinase (PI3K)/Akt/survivin pathway. Treatment of FET DNRII cells with a PI3K inhibitor (LY294002) inhibited Akt phosphorylation and reduced survivin expression resulting in increased apoptosis in FET/DNRII cells. We also show that exogenous TGFβ increased apoptosis in FET cells through repression of the PI3K/Akt/survivin pathway during GFDS. These results indicate that the PI3K/Akt/survivin pathway is blocked by TGFβ signaling and that loss of autocrine TGFβ leads to increased cell survival during GFDS through the novel linkage of TGFβ-mediated repression of survivin expression. Inhibition of survivin function by dominant-negative approaches showed that this inhibitor of apoptosis family member is critical to cell survival in the FET/DNRII cells, thus indicating the importance of this target for TGFβ-mediated apoptosis. [Cancer Res 2008;68(9):3152–60]
Avoiding Side Effects in Implementing Health Insurance Reform
Authors: Mark V. Pauly
Journal: New England Journal of Medicine (2010)

All U.S. health insurance reform proposals currently being discussed now include changes in the way insurers treat some people with above-average health risks. In most states, insurers who sell policies directly to individuals now charge premiums based to some extent on characteristics thought to predict the risk of high-cost conditions; insurers also exclude some or all preexisting conditions from coverage and simply refuse to cover some people. Without such “risk rating” and coverage exclusions, insurers would be subject to substantial adverse selection — that is, consumers would seek them out primarily if and when they became ill and therefore represented . . .
Validation of ERCC1-XPF Immunodetection – Letter
Authors: Ken André Olaussen, Jean-Charles Soria
Journal: Cancer Research (2010)

The monoclonal antibody 8F1 has allowed clinically relevant immunodetection of ERCC1 in formalin-fixed paraffin-embedded (FFPE) tumors (1–3). The article by Bhagwat and colleagues (4) acknowledges 8F1 recognition of ERCC1 (His-tagged protein recognition and pull-down of ERCC1-XPF complex in immunoprecipitation). However, investigating normal (C5RO), XPF (XP51RO and XP2YO), XPA (XP25RO cells), and ERCC1 (165TOR cells)-mutated skin fibroblasts, they report 8F1 as unsuitable for immunohistochemistry. In Western blots, they observed an additional band with extremely close molecular weight (double band). Surprisingly, they did not do exploratory experiments (mass spectrometry, crystallography) to elucidate the nature of the band (chemically modified ERCC1?) and recommend the use of the polyclonal FL297 antibody (4).Here, we evaluated a panel of cell lines for the presence of the alleged band in Western blots. Fibroblasts (HEL299, IMR90), lung carcinoma cells (A549, H1299, H1563, H1650, H1651, H1793, H1975, H2228, H2342, BEN, HCC827), and other epithelial carcinoma cells (HeLa, SKBR3, MCF7, HCT116) were screened. The 8F1 Western blot from a selection of these cell lines is shown in Fig. 1A. We did not observe in any of our cells a higher band very close to ERCC1 (at the molecular weight described by Bhagwat and colleagues), suggesting that it is rarely present in carcinoma cells. The 8F1 signal was also correlated with ERCC1 mRNA expression in the cells (Fig. 1A), which was confirmed by public transcriptome data (GEO: GSE10843), suggesting antibody specificity.Small interfering RNA (siRNA) or short hairpin RNA (shRNA)-mediated ERCC1 down-regulation in Western and immunohistochemistry-like techniques on FFPE cell pellets (A549, H1299, H1975) clearly led to a decrease in ERCC1 signal (Fig. 1B and C). As expected, 8F1 showed a nuclear staining in the immunohistochemistry-like conditions in control cells, whereas the FL297 antibody showed mainly cytoplasmic staining (as reported in Bhagwat and colleagues in FFPE cells using FL297; see their Fig. 5, particularly the lowest panels).In FFPE tissue sections of non-small cell lung carcinoma (NSCLC) patients, we frequently observed a cytoplasmic staining with FL297 and a nuclear staining with 8F1 (Fig. 1D). Consequently, we believe that the 8F1 antibody is an acceptable tool to determine nuclear ERCC1 protein expression in human FFPE tissues of solid tumors of epithelial origin, whereas FL297 leads to a puzzling cytoplasmic staining. Interestingly, ERCC1 mutations in 165TOR cells prevent the nuclear localization of the protein (5), but the role of cytoplasmic ERCC1 in cancer remains unknown.No potential conflicts of interest were disclosed.
Evidence will help achieve consensus
Authors: Peter Goldblatt
Journal: BMJ (2006)

Iversen and colleagues identify the problems that UK researchers have in gaining access to confidential patient information without consent.1 The issues that arise are both legal and ethical. These are summarised in Confidentiality: NHS Code of Practice .2 This document identifies four main areas of law that constrain or regulate the use and disclosure of personal health information: common law of confidentiality, the Data Protection Act 1998, the Human Rights Act 1998, and administrative law. At present, disclosure of identifiable information without consent is permitted for medical purposes other than direct healthcare (research and epidemiology) if …
Ventricular Fibrillation Induced by an Implanted Cardiac Pacemaker
Authors: Leslie W. Ottinger, W. Gerald Austen, Edwin O. Wheeler
Journal: New England Journal of Medicine (1965)

THE introduction of an artificial device or material into the body is attended by problems associated with its failure. This may result in functional or anatomic phenomena requiring special methods of diagnosis and treatment. One such problem found with implanted cardiac pacemakers is that of pacemaker-induced arrhythmias. This paper will detail the successful management of such an arrhythmia and outline certain principles applicable to the emergency handling of this kind of pacemaker failure.Case ReportA 69-year-old man (M.G.H. 95097) was first admitted to the hospital in January, 1964. His complaints were of fainting spells, severe dyspnea on exertion and . . .
Choosing an antidepressant.
Authors: P Crome, R Braithwaite, B Newman, S Montgomery
Journal: BMJ (1978)

with angina pectoris, especially for patients unable to tolerate beta-blockers.Even if the occasional patient does develop side effects such as those described, the fact that these are easily recognised and, in our experience to date, have always been reversible should provide reassurance to those who have doubts about prescribing this drug because of the development of neuropathy.
Low-Pressure Cardiac Tamponade
Authors: ELLIOTT M. ANTMAN
Journal: Annals of Internal Medicine (1979)

An elderly man developed cardiac tamponade from a tuberculous pericardial effusion but without such typical manifestations as pulsus paradoxus and jugular-vein distension. This case illustrates the difficulties in clinical recognition of low-pressure cardiac tamponade, which can develop in the presence of dehydration and hypovolemia. The hemodynamic factors that account for this phenomenon are discussed.
MTAS—Indian style
Authors: Ajit Singh Kashyap, Kuldip Parkash Anand, Surekha Kashyap
Journal: BMJ (2007)

He was a callow young doctor who had been posted to a 100 bed, government district hospital in a small town in central India. In the hospital he came across a young woman doctor who had recently graduated from medical college. They decided to get married before their postings to remote corners of the country according to the prevailing government service rules. Their parents were vehemently opposed to …
Oxygen as a driving gas for nebulisers: safe or dangerous?
Authors: J W Hadfield, S J Stinchcombe, J R Bateman
Journal: BMJ (1984)

increased attention to dietary intake for prolonged periods may influence the patient's eating habits.' Clinical details of patients were not included because of limitations of space but they have been reported elsewhere.'None had an ileostomy or colostomy or had undergone recent surgery; their treatment and weight had remained constant in the preceding two months.We agree with Mr Jourdan's observations that many thin patients with inactive Crohn's disease have healthy appetites, as shown in our study.This is in contrast to previous observations, in which inadequate oral intakes were thought to be the cause of weight loss, emaciation, and growth failure.
Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess.
Authors: S Refetoff, V S Fang, J S Marshall, N I Robin
Journal: Journal of Clinical Investigation (1976)

It has been previously suggested that inherited thyroxine-binding globulin (TBG) abnormalities in man may be due to mutations at a single X-chromosome-linked locus controlling TBG synthesis. However, abnormalities in TBG degradation have not been excluded. The availability of purified human TBG and its successful labeling with radioiodide allowed us to examine such possibility. Human TBG was purified by affinity chromatography, labeled under sterile conditions with 131I or 125I,, and mixed with [125I]thyroxine (T4) or [131I]T4, respectively, before their intravenous injection. Blood and urine samples were collected over a 10-day period, and the turnover parameters were calculated. In eight normal volunteers mean values +/-SD for TBG and T4 respectively, were as follows: Half time (t1/2) 5.3 +/- 0.4 and 7.0 +/- 0.6 days; distribution space (DS) 7.2 +/- 1.0 and 10.8 +/- 1.2 liters; and total daily degradation (D) 0.211 +/- 0.053 and 0.088 +/- 0.011 mumol/day. In all subjects, t1/2 of TBG was shorter than that of T4; and the DS was smaller. 2.4 mol of TBG was degraded for each mole of T4. In five of six subjects from four families, comprising hemizygous and heterozygous carriers of TBG absence, decrease, and excess, the t1/2 and DS for TBG were within the normal range. The D of TBG was proportional to the serum concentration of the protein. Changes in the T4 kinetics in these patients were compatible with euthyroidism and with the known alterations in the extrathyroidal T4 pool associated with the changes in serum TBG concentration. A striking decrease in the t1/2 of TBG was found only in a patient with acquired diminution in TBG concentration and in patients with thyrotoxicosis or other conditions apparently unrelated to thyroid dysfunction. TBG t1/2 was 2.5 days in a patient with multiple myeloma and 3.6 days in two patients with thyrotoxicosis. Decreased TBG t1/2 was also observed in three of six patients with nonthyroidal pathology and was associated with an increase in TBG D disproportionate to their level of serum TBG. These studies indicate that changes in TBG concentration in patients with X-chromosome-linked TBG abnormalities are due to alterations in its rate of synthesis. In other conditions, abnormalities of TBG degradation and/or rate of synthesis may be found.
Prophylactic Mastectomy for Prevention of the Second Primary
Authors: T. Brannon Hubbard
Journal: JAMA (1967)

The exact cause of human breast cancer is unknown. Possibly several factors operate conjointlygenetic, environmental, viral, or hormonal. It is thus not surprising that cancer can arise in both breasts. In fact, when a woman has had cancer of one breast, her risk of developing one in the other is five times that of a woman who has never had mammary cancer. Approximately 1% of patients with breast cancer are first seen with simultaneous bilateral cancers. These should be treated either by bilateral mastectomy at one operation or at least during the same period of hospitalization. Another group develop a cancer in the second breast months or years after their first mastectomy. Although conceivably these later lesions could be metastatic from the first, one should, in the absence of other known metastases, treat them optimistically as though they were new primary tumors. That the majority are new primaries is suggested
Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography
Authors: Fabien Hyafil, Jean-Christophe Cornily, Jonathan E Feig, Ronald Gordon, Esad Vucic, Vardan Amirbekian, Edward A Fisher, Valentin Fuster, Laurent J Feldman, Zahi A Fayad
Journal: Nature Medicine (2007)
The Two-Step Exercise Electrocardiogram
Authors: CHARLES K. FRIEDBERG, HARRY L. JAFFE, LEON PORDY, KENNETH CHESKY
Journal: Circulation (1962)

A double-blind study was made to evaluate the two-step exercise electrocardiographic test (Master) as a means of differentiating between anginal and nonanginal chest pain in 100 consecutive patients. A high percentage of false-positive results in nonanginal cases and a number of false negatives in anginal cases greatly impaired the usefulness of the test for this purpose. When Master's criterion of an ST depression of 0.5 mm. or more was employed, there were 39 per cent false positives and 12 per cent false negatives. Stricter criteria progressively diminished the number of false positives, but resulted in increasing numbers of false negatives. Even if 1 mm. or more of ST depression was required, there were 8 per cent false positives and 43 per cent false negatives. There were no false positives only when the ST segment was depressed 2 mm. or more. Although an ischemic type of ST depression may be more significant for angina pectoris than the J type, in our series ischemic ST depressions also occurred more frequently than the J type in false-positive tests in nonanginal patients. The new criteria of Master and Rosenfeld were not more satisfactory than the previous criteria recommended. There are relatively few cases in which an objective two-step test is necessary to aid in the differentiation of anginal and nonanginal pain, since an unequivocal diagnosis of angina pectoris or nonanginal pain was made in 86 per cent of cases independently by at least two observers, on the basis of a single interview, and since this percentage could undoubtedly have been increased by further interviews concerning the effect of effort and of nitroglycerin. Insofar as confirmation of a clinical diagnosis of angina pectoris by an objective exercise test is desirable, an ST-segment depression of at least 1 mm. usually offers such confirmation. However, this degree of ST-segment depression is often absent in unequivocal cases of angina pectoris and conversely may be occasionally present in patients with nonanginal pain.