tbuckley/cabot-search huggingface dataset:
Some recent contributions from the electron microscope laboratories.
Authors: T H Flewett
Journal: BMJ (1972)

We integrated genomic and bioinformatic analyses, using data from the largest genome-wide association study of cocaine dependence (CD; <i>n</i> = 6546; 82.37% with CD; 57.39% male) and the largest postmortem gene-expression sample of individuals with cocaine use disorder (CUD; <i>n</i> = 36; 51.35% with CUD; 100% male). Our genome-wide analyses identified one novel gene (<i>NDUFB9</i>) associated with the genetic predisposition to CD in African-Americans. The genetic architecture of CD was similar across ancestries. Individual genes associated with CD demonstrated modest overlap across European-Americans and African-Americans, but the genetic liability for CD converged on many similar tissue types (brain, heart, blood, liver) across ancestries. In a separate sample, we investigated the neuronal gene expression associated with CUD by using RNA sequencing of dorsal–lateral prefrontal cortex neurons. We identified 133 genes differentially expressed between CUD case patients and cocaine-free control subjects, including previously implicated candidates for cocaine use/addiction (<i>FOSB</i>, <i>ARC</i>, <i>KCNJ9/GIRK3</i>, <i>NR4A2</i>, <i>JUNB</i>, and <i>MECP2</i>). Differential expression analyses significantly correlated across European-Americans and African-Americans. While genes significantly associated with CD via genome-wide methods were not differentially expressed, two of these genes (<i>NDUFB9</i> and <i>C1qL2</i>) were part of a robust gene coexpression network associated with CUD involved in neurotransmission (GABA, acetylcholine, serotonin, and dopamine) and drug addiction. We then used a “guilt-by-association” approach to unravel the biological relevance of <i>NDUFB9</i> and <i>C1qL2</i> in the context of CD. In sum, our study furthers the understanding of the genetic architecture and molecular neuropathology of human cocaine addiction and provides a framework for translating biological meaning into otherwise obscure genome-wide associations. <b>SIGNIFICANCE STATEMENT</b> Our study further clarifies the genetic and neurobiological contributions to cocaine addiction, provides a rapid approach for generating testable hypotheses for specific candidates identified by genome-wide research, and investigates the cross-ancestral biological contributions to cocaine use disorder/dependence for individuals of European-American and African-American ancestries.
KLF6 Gene and Early Melanoma Development in a Collagen I-Rich Extracellular Environment
Authors: S. J. Huh, Y.-L. Chen, S. L. Friedman, J. Liao, H.- J. S. Huang, W. K. Cavenee, G. P. Robertson
Journal: JNCI Journal of the National Cancer Institute (2010)

A putative tumor suppressor gene at chromosome 10p15, which contains KLF6 and other genes, is predicted to be lost during melanoma development, and its identity is unknown. In this study, we investigated the biological roles and identity of this tumor suppressor gene. The human UACC 903 melanoma cell line containing introduced DNA fragments from the 10p15 region with (10E6/3, 10E6/11, and 10E6/18) and without (10ER4S.2/1) the tumor suppressor gene was used. Xenograft tumors were generated in a total of 40 mice with melanoma cell lines, and tumor size was measured. Cells were cultured on plastic or a gel of type I collagen. Viability, proliferation, and apoptosis were assessed. Expression of KLF6 protein was assessed by immunohistochemistry and immunoblot analysis. Expression of phosphorylated Erk1/2 and cyclin D1 was assessed by immunoblot analysis. Protein expression of KLF6 was inhibited with small interfering RNA (siRNA). KLF6 protein expression was assessed in 17 human nevi and human melanoma specimens from 29 patients. Statistical analyses were adjusted for multiple comparisons by use of Dunnett method. All statistical tests were two-sided. Melanoma cells containing KLF6 generated smaller subcutaneous xenograft tumors with fewer proliferating cells than control cells. When grown on collagen 1, viability of cells with ectopic KLF6 expression (72%) was lower than that of control cells (100%) (group difference = −28%, 95% confidence interval = −31.3% to −25.2%, P < .001). Viability of melanoma cells with or without the KLF6 tumor suppressor gene on plastic dishes was similar. When KLF6 expression was inhibited with KLF6 siRNA, viability of cells with the tumor suppressor gene on collagen I gel increased compared with that of control cells carrying scrambled siRNA. KLF6 protein was detected in all nevi examined but not in human metastatic melanoma tissue examined. Ectopic expression of KLF6 protein in melanoma cells grown on collagen I decreased levels of phosphorylated Erk1/2 and cyclin D1 in the mitogen-activated protein kinase signaling pathway. In melanoma cells, the tumor suppressor gene at 10p15 appears to be KLF6 . Signaling from the collagen I-rich extracellular matrix appears to be involved in the tumor suppressive activity of KLF6 protein.
Pericardial Fat Is Associated With Atrial Fibrillation Severity and Ablation Outcome
Authors: Christopher X. Wong, Hany S. Abed, Payman Molaee, Adam J. Nelson, Anthony G. Brooks, Gautam Sharma, Darryl P. Leong, Dennis H. Lau, Melissa E. Middeldorp, Kurt C. Roberts-Thomson, Gary A. Wittert, Walter P. Abhayaratna, Stephen G. Worthley, Prashanthan Sanders
Journal: Journal of the American College of Cardiology (2011)
Some Observations on Medical Research
Authors: I. H. Page
Journal: CA A Cancer Journal for Clinicians (1966)

to the squid who swims backward, all the time emitting a cloud of ink.Loading the discipline of discovery with mediocrity is a very real danger.Believe me when I tell you one of the most unpleasant parts of research is to persuade nonscientific mediocre people that scientists can be mediocre too.This is the hazard of directing science through the consensus methods of committees.
Incidence and outcome of convulsive status epilepticus in Kenyan children: a cohort study
Authors: Manish Sadarangani, Claire Seaton, J Anthony G Scott, Bernhards Ogutu, Tansy Edwards, Agnes Prins, Hellen Gatakaa, Richard Idro, James A Berkley, Norbert Peshu, Brian G Neville, Charles R Newton
Journal: The Lancet Neurology (2008)

BackgroundConvulsive status epilepticus (CSE) is the most common neurological emergency in childhood and is often associated with fever. In sub-Saharan Africa, the high incidence of febrile illnesses might influence the incidence and outcome of CSE. We aimed to provide data on the incidence, causes, and outcomes of childhood CSE in this region.MethodsBetween March, 2006, and June, 2006, we studied all children who had been admitted with CSE to a Kenyan rural district hospital in 2002 and 2003. Confirmed CSE had been observed directly; probable CSE was inferred from convulsions on arrival, requirement for phenobarbital or phenytoin, or coma with a recent history of seizures. We estimated the incidence with linked demographic surveillance, and risk factors for death and neurological sequelae were analysed by multivariable analysis.FindingsOf 388 episodes of CSE, 155 (40%) were confirmed CSE and 274 (71%) were caused by an infection. The incidence of confirmed CSE was 35 (95% CI 27–46) per 100 000 children per year overall, and was 52 (21–107) and 85 (62–114) per 100 000 per year in children aged 1–11 months and 12–59 months, respectively. The incidence of all CSE was 268 (188–371) and 227 (189–272) per 100 000 per year in these age-groups. 59 (15%) children died in hospital, 81 (21%) died during long-term follow-up, and 46 (12%) developed neurological sequelae. Mortality of children with confirmed CSE while in hospital was associated with bacterial meningitis (adjusted relative risk [RR]=2·6; 95% CI 1·4–4·9) and focal onset seizures (adjusted RR=2·4; 1·1–5·4), whereas neurological sequelae were associated with hypoglycaemia (adjusted RR=3·5; 1·8–7·1) and age less than 12 months (adjusted RR=2·5; 1·2–5·1).InterpretationPrevention of infections and appropriate early management of seizures might reduce the incidence and improve the outcome of CSE in children in sub-Saharan Africa.
Persistent reduction in left ventricular asynergy in patients with acute myocardial infarction by intravenous infusion of nitroglycerin.
Authors: B I Jugdutt, B A Sussex, J W Warnica, R E Rossall
Journal: Circulation (1983)

Intravenous nitroglycerin (NG) infusion in patients with acute myocardial infarction (AMI) has been shown to improve left ventricular function and myocardial perfusion and to decrease ischemic injury and creatine kinase (CK) indexes of infarct size. To determine whether early NG infusions in patients with AMI decreases the extent of left ventricular asynergy, we used two-dimensional echocardiography to measure asynergic segments (akinesis and/or dyskinesis) at four serial short-axis levels from base to apex (mitral, M; chordal, C; midpapillary, MP; low papillary, LP) in 22 patients with a first anterior AMI. Patients were randomized between infusions of NG (n = 11) or 5% dextrose in water (controls, n = 11) within 5.6 hr after the onset of pain. NG infusion rates were titrated to lower mean arterial pressure to an average level of 7% below control (but not below 80 mm Hg) and were maintained at this level for the duration of the infusions (39 hr). After NG, left ventricular function improved as left ventricular filling pressure decreased (p less than .005), and sigma ST on precordial ST segment mapping decreased (p less than .001). These parameters did not change in control subjects. Computed CK infarct size was smaller in the NG group than in the control group (p less than .05). Before the infusions, the mean extent of left ventricular asynergy (% left ventricular circumference) were similar in both groups: M, 18% vs 21%; C, 22% vs 23%; MP, 26% vs 24%; LP, 32% vs 29%. In addition, the computed total left ventricular asynergy (% surface area) was also similar for these two groups before therapy (25% vs 25%). There was no change in left ventricular asynergy from pretreatment values by 1 hr and 10 days among control subjects: M, 18% vs 18% vs 17%; C, 22% vs 22%; MP, 26% vs 26% vs 22%; LP, 32% vs 33% vs 33%; total 25% vs 25% vs 24% (multiple measures analysis of variance). In contrast, there was a significant decrease (p less than .001) in left ventricular asynergy from pretreatment values by 1 hr and 10 days with NG: M, 21% vs 10% vs 8%; C, 23% vs 12% vs 10%; MP, 24% vs 13% vs 9%; LP, 29% vs 14% vs 10%; total, 25% vs 12% vs 9%.(ABSTRACT TRUNCATED AT 400 WORDS)
Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement
Authors: S. Guiu, S. Michiels, F. André, J. Cortes, C. Denkert, A. Di Leo, B.T. Hennessy, T. Sorlie, C. Sotiriou, N. Turner, M. Van de Vijver, G. Viale, S. Loi, J.S. Reis-Filho
Journal: Annals of Oncology (2012)
Dissociative symptoms and REM sleep
Authors: Dalena van Heugten-van der Kloet, Harald Merckelbach, Steven Jay Lynn
Journal: Behavioral and Brain Sciences (2013)

Abstract Llewellyn has written a fascinating article about rapid eye movement (REM) dreams and how they promote the elaborative encoding of recent memories. The main message of her article is that hyperassociative and fluid cognitive processes during REM dreaming facilitate consolidation. We consider one potential implication of this analysis: the possibility that excessive or out-of-phase REM sleep fuels dissociative symptomatology. Further research is warranted to explore the psychopathological ramifications of Llewellyn's theory.
Risk of Emergency Care, Hospitalization, and ICU Stays for Acute Asthma among Recipients of Salmeterol
Authors: STEPHAN F. LANES, LEE L. LANZA, CHARLES E. WENTWORTH
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We used automated health insurance claims records of a New England insurer to assess the relation between salmeterol and severe nonfatal asthma. We identified 61,712 members who received a β -agonist from January 1, 1993 to August 31, 1995, including 2,708 recipients of salmeterol. Compared with recipients of other β -agonists, future salmeterol recipients had higher rates of asthma hospitalization and dispensings of asthma medications during the year before they received salmeterol. We selected as a comparison group 3,825 recipients of sustained-release theophylline. We defined a baseline period as the year before the start of the follow-up period, and we characterized patients according to age, sex, calendar period, presence of baseline hospitalizations for asthma, presence of chronic obstructive pulmonary disease (COPD), and baseline dispensings of asthma medications. After adjusting for baseline factors, incidence rates of severe asthma in the salmeterol group were not elevated for emergency care (rate ratio estimate [RR] = 0.69, 95% confidence intervals [CI] = 0.42, 1.11), hospitalization (RR = 1.09, 95% CI = 0.60, 1.98), or intensive care unit (ICU) stays (RR = 0.81, 95% CI = 0.25, 2.62). We conclude that salmeterol was prescribed preferentially to high-risk patients and, after adjusting for baseline risk, salmeterol recipients did not have a greater risk than theophylline recipients of severe nonfatal asthma.
Deficiencies of Human Complement Component C4a and C4b and Heterozygosity in Length Variants of RP-C4-CYP21-TNX (Rccx) Modules in Caucasians
Authors: Carol A. Blanchong, Bi Zhou, Kristi L. Rupert, Erwin K. Chung, Karla N. Jones, Juan F. Sotos, William B. Zipf, Robert M. Rennebohm, C. Yung Yu
Journal: The Journal of Experimental Medicine (2000)

The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.
Vaccination with DNA Encoding an Immunodominant Myelin Basic Protein Peptide Targeted to Fc of Immunoglobulin G Suppresses Experimental Autoimmune Encephalomyelitis
Authors: Anna Lobell, Robert Weissert, Maria K. Storch, Cecilia Svanholm, Katrien L. de Graaf, Hans Lassmann, Roland Andersson, Tomas Olsson, Hans Wigzell
Journal: The Journal of Experimental Medicine (1998)

We explore here if vaccination with DNA encoding an autoantigenic peptide can suppress autoimmune disease. For this purpose we used experimental autoimmune encephalomyelitis (EAE), which is an autoaggressive disease in the central nervous system and an animal model for multiple sclerosis. Lewis rats were vaccinated with DNA encoding an encephalitogenic T cell epitope, guinea pig myelin basic protein peptide 68–85 (MBP68–85), before induction of EAE with MBP68–85 in complete Freund's adjuvant. Compared to vaccination with a control DNA construct, the vaccination suppressed clinical and histopathological signs of EAE, and reduced the interferon γ production after challenge with MBP68–85. Targeting of the gene product to Fc of IgG was essential for this effect. There were no signs of a Th2 cytokine bias. Our data suggest that DNA vaccines encoding autoantigenic peptides may be useful tools in controlling autoimmune disease.
Involvement of Disulfide Bond Formation in the Activation of Heparanase
Authors: Siro Simizu, Takehiro Suzuki, Makoto Muroi, Ngit Shin Lai, Satoshi Takagi, Naoshi Dohmae, Hiroyuki Osada
Journal: Cancer Research (2007)

Abstract Heparanase is overexpressed in many solid tumor cells and is capable of specifically cleaving heparan sulfate, and this activity is associated with the metastatic potential of tumor cells; however, the activation mechanism of heparanase has remained unknown. In this study, we investigated the link between disulfide bond formation and the activation of heparanase in human tumor cells. Mass spectrometry analysis of heparanase purified from a conditioned medium of human fibrosarcoma cells revealed two disulfide bonds, Cys127-Cys179 and Cys437-Cys542, and one S-cysteinylation at the Cys211 residue. It was shown that, although the formation of the Cys127-Cys179 bond and S-cysteinylation at Cys211 have little effect on heparanase function, the disulfide bond between Cys437 and Cys542 is necessary for the secretion and activation of heparanase. Thus, the present findings will provide a basis for the further refinement of heparanase structural studies and for the development of novel heparanase inhibitors. [Cancer Res 2007;67(16):7841–9]
Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy
Authors: Cissy Chenyi Zhou, Shakil Ahmad, TieJuan Mi, Lingwei Xia, Shahrzad Abbasi, Peter W. Hewett, ChunXiao Sun, Asif Ahmed, Rodney E. Kellems, Yang Xia
Journal: Circulation Research (2006)

Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.
Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2.
Authors: J R Zucali, C A Dinarello, D J Oblon, M A Gross, L Anderson, R S Weiner
Journal: Journal of Clinical Investigation (1986)

Granulocyte-macrophage colony-stimulating activity (GM-CSA) can be produced by a variety of normal cell types including mononuclear phagocytes, activated T lymphocytes, endothelial cells, and fibroblasts. Recent evidence shows that a major role of the monocyte-macrophage is the recruitment of environmental cells, i.e., fibroblasts, to produce GM-CSA. In this study we have identified interleukin 1 (IL-1) as a monokine that stimulates fibroblasts to produce and release GM-CSA and prostaglandin E2 (PGE2). Both purified human monocyte-derived IL-1 and human recombinant IL-1 (10(-10) M) can be substituted for monocyte-conditioned medium in stimulating fibroblast GM-CSA and PGE2 production. Both forms of IL-1 stimulate fibroblasts to produce GM-CSA and PGE2 in a dose-dependent fashion. The fibroblast-stimulating activity found in monocyte-conditioned medium was completely blocked by anti-IL-1. We conclude that monocytes produce IL-1, and that monocyte-derived IL-1 induces fibroblasts to produce GM-CSA and PGE2.
Tumor Cell Adhesion As a Risk Factor for Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma
Authors: Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Mark A. Cappel, Mark R. Pittelkow, Clark C. Otley, Nille Behrendt, Ditte M. Saunte, Jorgen Lock-Andersen, Louis A. Schenck, Amy L. Weaver, Vera J. Suman
Journal: Journal of Clinical Oncology (2015)

Purpose Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma. Patients and Methods Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables. Results ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk). Conclusion The addition of cell adhesion–linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.
Genetic susceptibility to psoriasis: an emerging picture
Authors: Rhodri Smith, Richard B Warren, Christopher EM Griffiths, Jane Worthington
Journal: Genome Medicine (2009)

Psoriasis is recognized as a complex disease for which multiple genetic and non-genetic factors influence susceptibility. The major susceptibility locus resides in the MHC class I region and, until relatively recently, evidence for non-MHC loci was inconsistent. Like many common diseases, knowledge of the genetic basis of this condition has been advanced dramatically in recent times with the advent of genome-wide association studies using single nucleotide polymorphisms. Here, we give an overview of current knowledge of genetic risk factors for psoriasis and consider emerging studies that may further add to our understanding of the genetic basis of the disease.