tbuckley/cabot-search huggingface dataset:
AGGRESSION, GUILT AND CATAPLEXY
Authors: MAX LEVIN
Journal: American Journal of Psychiatry (1959)

Cataplexy may be evoked by impulses of aggression associated with guilt. The aggression may be naked and undisguised, as in hunting and fishing, and in boxing, where the object is to hurt and paralyse one's opponent. Or it may be symbolic, as in those sports where the object is to defeat the opponent, not to hurt him. Finally, it may only be that benign aggression that is expressed in practical jokes and some kinds of play. Cataplexy, in all these cases, is a manifestation of conditioned inhibition, a response to the guilt that attends aggression even when it is only unconscious.
Inhibitory Effects of Phytohemagglutinin on Growth of Leukemia Lymphoblasts L5178Y In Vitro and In Vivo2
Authors: T. J. Yang
Journal: JNCI Journal of the National Cancer Institute (1975)

Phytohemagglutinin (PHA) inhibited the growth of mouse leukemia Iymphoblasts L5178Y in culture. RNA synthesis was repressed significantly within the first hour, and the rates of DNA and protein synthesis were significantly decreased within the second hour; maximum inhibition occurred after 24 hours. The ability of the cells to form colonies in soft agar was limited to a greater extent at much lower PHA con- centrations. The cells lost their tumorigenicity in syngeneic DBA/2 mice after 4 hours of PHA treatment, when the viability was not appreciably decreased. The cultures of a PHA-resistant strain derived from a resistant colony cloned from the PHA-containing soft agar plate showed increased resistance toward PHA. A fourfold increase in PHA concentration was needed for the same rate of inhibition of the original cell line to be attained.
Metabolism of the EGFR tyrosin kinase inhibitor gefitinib by cytochrome P450 1A1 enzyme in EGFR-wild type non small cell lung cancer cell lines
Authors: Roberta R Alfieri, Maricla Galetti, Stefano Tramonti, Roberta Andreoli, Paola Mozzoni, Andrea Cavazzoni, Mara Bonelli, Claudia Fumarola, Silvia La Monica, Elena Galvani, Giuseppe De Palma, Antonio Mutti, Marco Mor, Marcello Tiseo, Ettore Mari, Andrea Ardizzoni, Pier Petronini
Journal: Molecular Cancer (2011)

Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) especially effective in tumors with activating EGFR gene mutations while EGFR wild-type non small cell lung cancer (NSCLC) patients at present do not benefit from this treatment.The primary site of gefitinib metabolism is the liver, nevertheless tumor cell metabolism can significantly affect treatment effectiveness.In this study, we investigated the intracellular metabolism of gefitinib in a panel of EGFR wild-type gefitinib-sensitive and -resistant NSCLC cell lines, assessing the role of cytochrome P450 1A1 (CYP1A1) inhibition on gefitinib efficacy. Our results indicate that there is a significant difference in drug metabolism between gefitinib-sensitive and -resistant cell lines. Unexpectedly, only sensitive cells metabolized gefitinib, producing metabolites which were detected both inside and outside the cells. As a consequence of gefitinib metabolism, the intracellular level of gefitinib was markedly reduced after 12-24 h of treatment. Consistent with this observation, RT-PCR analysis and EROD assay showed that mRNA and activity of CYP1A1 were present at significant levels and were induced by gefitinib only in sensitive cells. Gefitinib metabolism was elevated in crowded cells, stimulated by exposure to cigarette smoke extract and prevented by hypoxic condition. It is worth noting that the metabolism of gefitinib in the sensitive cells is a consequence and not the cause of drug responsiveness, indeed treatment with a CYP1A1 inhibitor increased the efficacy of the drug because it prevented the fall in intracellular gefitinib level and significantly enhanced the inhibition of EGFR autophosphorylation, MAPK and PI3K/AKT/mTOR signalling pathways and cell proliferation.Our findings suggest that gefitinib metabolism in lung cancer cells, elicited by CYP1A1 activity, might represent an early assessment of gefitinib responsiveness in NSCLC cells lacking activating mutations. On the other hand, in metabolizing cells, the inhibition of CYP1A1 might lead to increased local exposure to the active drug and thus increase gefitinib potency.
An Immunotolerant HER-2/<i>neu</i>Transgenic Mouse Model of Metastatic Breast Cancer
Authors: Hong Song, Karineh Shahverdi, David L. Huso, Yuchuan Wang, James J. Fox, Robert F. Hobbs, Barjor Gimi, Kathleen L. Gabrielson, Martin G. Pomper, Benjamin M. Tsui, Zaver Bhujwalla, R. Todd Reilly, George Sgouros
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Animal models of breast cancer metastases that recapitulate the pattern of metastatic progression seen in patients are lacking; metastatic breast cancer models do not currently exist for evaluation of immune-mediated therapies. We have developed and characterized a preclinical model for the evaluation of immune-mediated metastatic breast cancer therapies. Experimental Design: The NT2.5 mammary tumor cell line was injected into the left cardiac ventricle of immunotolerant transgenic neu-N mice and athymic nu/nu mice. Metastatic progression was monitored by bioluminescent, small-animal magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography/computed tomography imaging, and also by histopathology. Antigen expression in normal organs and tumor metastases was evaluated by Western blot analysis and flow cytometry. Results: Left cardiac ventricle injection of NT2.5 cells yielded widespread metastases in bones, liver, and spleen. Three to four weeks after injection, mice exhibited hind limb paralysis and occasional abdominal enlargement. Bioluminescence imaging of metastatic progression was successful in nude mice but the bioluminescent cells were rejected in immunocompetent mice. Other imaging modalities allowed successful imaging of nonbioluminescent cells. Small-animal positron emission tomography imaging allowed visualization of disease, in vivo, in the bones and liver. Magnetic resonance imaging revealed initial dissemination of the tumor cells to the bone marrow. Small-animal single-photon emission computed tomography/computed tomography imaging identified metastatic bone lesions targeted by a radiolabeled antibody. Conclusion: The model closely recapitulates the pattern of metastatic spread in breast cancer. This immunotolerant metastatic model is a novel addition to existing breast cancer models and coupling the model with in vivo imaging greatly facilitates the evaluation of targeted immunotherapies of metastasis.
Effect of the Implantable Left Ventricular Assist Device on Neuroendocrine Activation in Heart Failure
Authors: Karen B. James, Patrick M. McCarthy, James D. Thomas, Rita Vargo, Robert E. Hobbs, Shelly Sapp, Emmanuel Bravo
Journal: Circulation (1995)

Background The HeartMate left ventricular assist device has been successfully used as a bridge to cardiac transplantation. Because many patients exhibit marked clinical improvement in their heart failure after HeartMate implantation, we studied the physiological effect of this device on the neurohormonal axis. Methods and Results In 13 patients awaiting transplant (mean cardiac index, 1.7±0.3 L · min −1 · m −2 ) who underwent HeartMate implantation, venous atrial natriuretic peptide, epinephrine, norepinephrine, plasma renin activity, angiotensin, and arginine vasopressin were measured immediately before insertion and at explant/transplantation. Mean time to explant was 86±40 days. All patients were taken off inotropic medications within 1 month. Mean cardiac index on support before explant was 3.1±0.9 L · min −1 · m −2 . Plasma renin activity decreased from 57±56 ng · mL −1 · h −1 at baseline (before insertion) to 3±3 ng · mL −1 · h −1 at explant (mean percent change, 92%; P &lt;.001). Angiotensin II level decreased from 237±398 U/L at baseline to 14±14 U/L at explant (mean percent change, 73%; P &lt;.001). Plasma epinephrine level fell from 6800±1323 pg/mL at baseline to 46±46 pg/mL at explant (mean percent change, 86%; P &lt;.001). Norepinephrine level decreased from 2953±1457 pg/mL at baseline to 518±290 pg/mL at explant (mean percent change, 79%; P &lt;.001). Atrial natriuretic peptide fell from baseline values of 227±196 to 168±40 pg/mL at explant (mean percent change, −49%; P =.519); and arginine vasopressin level decreased from 6±6 pg/mL at baseline to 0.8±0.5 pg/mL (mean percent change, 69%; P =.002). Conclusions We provide data supporting that the neurohormonal axis markedly improves after HeartMate implantation, providing biochemical confirmation of the improvement in hemodynamic status.
Accurate Classification of Diffuse Large B-Cell Lymphoma into Germinal Center and Activated B-Cell Subtypes Using a Nuclease Protection Assay on Formalin-Fixed, Paraffin-Embedded Tissues
Authors: Lisa M. Rimsza, George Wright, Mark Schwartz, Wing C. Chan, Elaine S. Jaffe, Randy D. Gascoyne, Elias Campo, Andreas Rosenwald, German Ott, James R. Cook, Raymond R. Tubbs, Rita M. Braziel, Jan Delabie, Tom P. Miller, Louis M. Staudt
Journal: Clinical Cancer Research (2011)

Abstract Classification of diffuse large B-cell lymphoma (DLBCL) into cell-of-origin (COO) subtypes based on gene expression profiles has well-established prognostic value. These subtypes, termed germinal center B cell (GCB) and activated B cell (ABC) also have different genetic alterations and overexpression of different pathways that may serve as therapeutic targets. Thus, accurate classification is essential for analysis of clinical trial results and planning new trials by using targeted agents. The current standard for COO classification uses gene expression profiling (GEP) of snap frozen tissues, and a Bayesian predictor algorithm. However, this is generally not feasible. In this study, we investigated whether the qNPA technique could be used for accurate classification of COO by using formalin-fixed, paraffin-embedded (FFPE) tissues. We analyzed expression levels of 14 genes in 121 cases of R-CHOP-treated DLBCL that had previously undergone GEP by using the Affymetrix U133 Plus 2.0 microarray and had matching FFPE blocks. Results were evaluated by using the previously published algorithm with a leave-one-out cross-validation approach. These results were compared with COO classification based on frozen tissue GEP profiles. For each case, a probability statistic was generated indicating the likelihood that the classification by using qNPA was accurate. When data were dichotomized into GCB or non-GCB, overall accuracy was 92%. The qNPA technique accurately categorized DLBCL into GCB and ABC subtypes, as defined by GEP. This approach is quantifiable, applicable to FFPE tissues with no technical failures, and has potential for significant impact on DLBCL research and clinical trial development. Clin Cancer Res; 17(11); 3727–32. ©2011 AACR.
Clinical and morphological signs of liver damadge in patients with pulmonary sarcoidosis
Authors: Marina Lebedeva, Irina Popova, Elena Popova, Andrew Ponomarev, Elena Arion
Journal: European Respiratory Journal (2011)

The aim  of our study was to identify clinical and morphological signs of liver damadge in patients with pulmonary sarcoidosis.   Patients and methods:  65 patients with morphologically proved pulmonary sarcoidosis were examined. Pulmonary function testing, high-resolution CT (HRCT), liver tests were evaluated. Biopsy of lung (65), liver (52) were performed. Biopsy of liver were performed if the signs of cytolisis and/or cholestasis were present.   Results:  65 patients had markers of active pulmonary sarcoidosis: respiratory failure which correlated with HRCT sings of activity such as ground - glass opaque (p=0,0053) and morphology of specific granulomatous, 52 patients also presented slight hepatomegaly, sings of cytolisis (AST 1,2-2,5 norms, ALT 1,3 – 2,7 norms) and/or cholestasis (GGT 1,6-3,4 norms) which correlated with morphological signs of liver granulematosis: the non-caseating granulomas were in all biopsies, three types of histologic change were found: inflammatory (78%) cholestatic (51%), and vascular (19%).Inflammatory changes included inflammation suggestive of chronic active hepatitis. Among those with cholestasis, 9 had a pattern of periductal fibrosis. Vascular changes consisted of sinusoidal dilatation (3 cases) and nodular regenerative hyperplasia (7 cases). No cirrhosis were found.   Conclusion:  Liver involvement can be considered as a marker of extra-pulmonary activity in pulmonary sarcoidosis.
Phase I study of granulocyte colony-stimulating factor in patients with transitional cell carcinoma of the urothelium.
Authors: J L Gabrilove, A Jakubowski, K Fain, J Grous, H Scher, C Sternberg, A Yagoda, B Clarkson, M A Bonilla, H F Oettgen
Journal: Journal of Clinical Investigation (1988)

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered at a dose of 1-60 micrograms/kg of body weight to 22 patients with transitional cell carcinoma before chemotherapy as part of a Phase I/II study. In all patients, a specific dose-dependent increase in the absolute neutrophil count (ANC) of 1.8-12 fold was seen. In addition, this augmentation in the ANC was accompanied by an increase in leukocyte alkaline phosphatase, a marker of secondary granule formation. In six of eight patients analyzed, an increase in bone marrow myeloid to erythroid cell ratio was seen. Day 14 peripheral blood cell derived colony forming unit granulocyte macrophage were also increased by day 6 of rhG-CSF treatment. Circulating levels of eosinophils and basophils were unchanged; however, a 10-fold increase in monocytes was observed in patients treated at the highest doses. There was also a small increase in CD3+ lymphocytes that was not dose dependent. Hemoglobin, hematocrit, and platelet count remained near baseline throughout the period of rhG-CSF administration. These findings demonstrate that rhG-CSF is a potent stimulus for normal neutrophil proliferation and maturation.
The Alzheimer's disease Beta-secretase enzyme, BACE1
Authors: Sarah L Cole, Robert Vassar
Journal: Molecular Neurodegeneration (2007)

The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of β-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing β-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences), and the pathogenic alterations in BACE1 that are observed in the diseased state.
Finding the Right Fit for Meal Planning
Authors: Marion J Franz
Journal: Diabetes Care (1993)

Nuttall (this issue, F.Q. Nuttall, p. 1039–42) is to be congratulated on articulating a constant CHO meal-planning approach that can be used by medical professionals and individuals with diabetes. Central to this approach is determining the usual amount of CHO eaten at meals and/or snacks by the person with diabetes, keeping that amount constant, and covering with the appropriate amount of insulin.
The Effect of Lipemia upon Tissue Oxygen Tension in Man
Authors: CLAUDE R. JOYNER, ORVILLE HORWITZ, PHYLLIS G. WILLIAMS
Journal: Circulation (1960)

The effect of varying levels of lipemia upon tissue oxygen tension has been investigated in human subjects with normal and decreased peripheral blood flow. Oxygen tension of the skin was determined during rapid clearing of lipemia to avoid the difficulties inherent in prolonged study over the several hours of increasing lipemia following a fat meal. Regardless of whether peripheral blood flow was normal or decreased, a mean increase of 21.7 per cent in skin oxygen tension occurred during heparin-induced clearing of plasma turbidity. In addition, skin oxygen tension increased during the spontaneous decline of lipemia in 1 subject. Oxygen tension was not increased after a saline placebo injection during lipemia or following heparin injections in subjects with "clear" fasting serum. The observed increase could not be attributed to changes in blood flow. Skin temperature remained stable during the experiments and the subject's response could not be correlated with skin blood flow as measured by the vasodilatation test. The increase in tissue oxygen tension that occurs during clearing of plasma seems most probably to be due to increased diffusion of oxygen to or from the erythrocytes.
Relationships Between Poverty and Psychopathology
Authors: E. Jane Costello, Scott N. Compton, Gordon Keeler, Adrian Angold
Journal: JAMA (2003)

Social causation (adversity and stress) vs social selection (downward mobility from familial liability to mental illness) are competing theories about the origins of mental illness.To test the role of social selection vs social causation of childhood psychopathology using a natural experiment.Quasi-experimental, longitudinal study.A representative population sample of 1420 rural children aged 9 to 13 years at intake were given annual psychiatric assessments for 8 years (1993-2000). One quarter of the sample were American Indian, and the remaining were predominantly white. Halfway through the study, a casino opening on the Indian reservation gave every American Indian an income supplement that increased annually. This increase moved 14% of study families out of poverty, while 53% remained poor, and 32% were never poor. Incomes of non-Indian families were unaffected.Levels of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, psychiatric symptoms in the never-poor, persistently poor, and ex-poor children were compared for the 4 years before and after the casino opened.Before the casino opened, the persistently poor and ex-poor children had more psychiatric symptoms (4.38 and 4.28, respectively) than the never-poor children (2.75), but after the opening levels among the ex-poor fell to those of the never-poor children, while levels among those who were persistently poor remained high (odds ratio, 1.50; 95% confidence interval, 1.08-2.09; and odds ratio, 0.91; 95% confidence interval, 0.77-1.07, respectively). The effect was specific to symptoms of conduct and oppositional defiant disorders. Anxiety and depression symptoms were unaffected. Similar results were found in non-Indian children whose families moved out of poverty during the same period.An income intervention that moved families out of poverty for reasons that cannot be ascribed to family characteristics had a major effect on some types of children's psychiatric disorders, but not on others. Results support a social causation explanation for conduct and oppositional disorder, but not for anxiety or depression.
The RNA-binding protein hnRNPLL induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA
Authors: Vicky Cho, Yan Mei, Arleen Sanny, Stephanie Chan, Anselm Enders, Edward M Bertram, Andy Tan, Christopher C Goodnow, T Andrews
Journal: Genome biology (2014)

Retention of a subset of introns in spliced polyadenylated mRNA is emerging as a frequent, unexplained finding from RNA deep sequencing in mammalian cells. Here we analyze intron retention in T lymphocytes by deep sequencing polyadenylated RNA. We show a developmentally regulated RNA-binding protein, hnRNPLL, induces retention of specific introns by sequencing RNA from T cells with an inactivating Hnrpll mutation and from B lymphocytes that physiologically downregulate Hnrpll during their differentiation. In Ptprc mRNA encoding the tyrosine phosphatase CD45, hnRNPLL induces selective retention of introns flanking exons 4 to 6; these correspond to the cassette exons containing hnRNPLL binding sites that are skipped in cells with normal, but not mutant or low, hnRNPLL. We identify similar patterns of hnRNPLL-induced differential intron retention flanking alternative exons in 14 other genes, representing novel elements of the hnRNPLL-induced splicing program in T cells. Retroviral expression of a normally spliced cDNA for one of these targets, Senp2, partially corrects the survival defect of Hnrpll-mutant T cells. We find that integrating a number of computational methods to detect genes with differentially retained introns provides a strategy to enrich for alternatively spliced exons in mammalian RNA-seq data, when complemented by RNA-seq analysis of purified cells with experimentally perturbed RNA-binding proteins. Our findings demonstrate that intron retention in mRNA is induced by specific RNA-binding proteins and suggest a biological significance for this process in marking exons that are poised for alternative splicing.
Using Cyclooxygenase-2 Inhibitors as Molecular Platforms to Develop a New Class of Apoptosis-Inducing Agents
Authors: J. Zhu
Journal: JNCI Journal of the National Cancer Institute (2002)

The cyclooxygenase-2 (COX-2) inhibitor celecoxib is thought to act as a chemopreventive agent by sensitizing cancer cells to apoptotic signals. Other COX-2 inhibitors, such as rofecoxib, are two orders of magnitude less potent than celecoxib at inducing apoptosis. The molecular structures of celecoxib and rofecoxib were used as starting points to examine the structural features that contribute to this discrepancy.We used a systematic chemical approach to modify the structures of celecoxib and rofecoxib to produce a series of compounds that were tested for their effects on the viability of human prostate cancer PC-3 cells and their ability to induce apoptosis in these cells. Cell viability was measured by the trypan blue dye exclusion assay, and apoptosis was measured by an enzyme-linked immunosorbent assay that quantifies DNA cleavage and by western blot detection of poly(ADP-ribose) polymerase (PARP) cleavage. Western blotting was used to monitor the effects of the compounds on phosphorylation of the serine/threonine kinase Akt and extracellular signal-regulated kinase 2 (ERK2), two components of celecoxib-induced apoptosis signaling. Monte Carlo simulations were used to molecularly model the surface electrostatic potential and electron density of selected compounds. All statistical tests were two-sided.The structural requirements for the induction of apoptosis in PC-3 cells were different from those for COX-2 inhibition. Structure-function analysis indicated that the induction of apoptosis by compounds derived from COX-2 inhibitors required a bulky terminal phenyl ring, a heterocyclic system with negative electrostatic potential, and a benzenesulfonamide or benzenecarboxamide moiety. These derivatives mediated apoptosis by facilitating the dephosphorylation of Akt and ERK2, irrespective of their COX-2 inhibitory activities.A new class of compounds that induce apoptosis by targeting Akt and ERK2 signaling pathways in human prostate cancer cells can be synthesized by modifying existing COX-2 inhibitors.