tbuckley/cabot-search huggingface dataset:
Differences in Platelet Enzyme Activity between Alcoholics and Nonalcoholics
Authors: B Tabakoff, P L Hoffman, J M Lee, T Saito, B Willard, F De Leon-Jones
Journal: New England Journal of Medicine (1988)

Blood platelets are an accessible tissue that reflects the activity of many enzymes found in the brain. To investigate the possible effect on such enzymes of long-term consumption of large quantities of ethanol, we assayed the activities of two enzymes, monoamine oxidase and adenylate cyclase, in platelet membranes of men with alcoholism and controls matched for sex and age. We also compared these two groups in terms of the inhibition of platelet monoamine oxidase activity by ethanol in vitro (400 mM), and in terms of the stimulation of adenylate cyclase activity by various agents. There was no significant difference in monoamine oxidase activity between the alcoholics and the controls. However, the inhibition of monoamine oxidase by ethanol was significantly higher in the platelets of alcoholics. The basal activity of adenylate cyclase was the same in platelets from the alcoholics and the controls, but the platelet adenylate cyclase activity after stimulation with guanine nucleotide, cesium fluoride, or prostaglandin E1 was significantly lower in alcoholics. These differences were not associated with age, race, smoking, or illicit drug use, and there was no significant correlation with the duration of problems with alcohol. The changes were long-lasting; cesium fluoride-stimulated adenylate cyclase activity was lower in alcoholic subjects who had abstained from alcohol for one to four years. Discriminant analysis showed that the use of values for the inhibition of monoamine oxidase activity by ethanol and cesium fluoride-stimulated adenylate cyclase activity correctly classified 75 percent of the alcoholics and 73 percent of the controls. These measures may be of value either as indexes of excessive alcohol consumption or as an indication of a predisposition to alcoholism.
Clinical impact of amphiregulin expression in EGFR wild-type non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.
Authors: M. Chang, J. Lee, C. Jung, Y. Park, J. Ahn, K. Park, M. Ahn
Journal: Journal of Clinical Oncology (2010)

7539 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have shown survival benefit in non-small cell lung cancer (NSCLC). Several studies have demonstrated the positive correlation between somatic mutation in the EGFR tyrosine kinase domain (exons 18-21) and clinical outcomes with EGFR-TKIs. However, some of the patients with wild-type (WT) EGFR also showed response to EGFR TKIs and remain stable disease. Recently, amphiregulin (AR) has been suggested as a predictive marker of EGFR-TKIs in WT EGFR NSCLC. The aim of this study was to evaluate the association between AR expression and EGFR-TKIs efficacy in WT EGFR NSCLC patients. Methods: Seventy-three patients with WT EGFR NSCLC were treated with EGFR-TKIs (gefitinib or erlotinib) between May 2005 and December 2008. AR expression was assessed by immunohistochemistry. Results: The clinical response to EGFR-TKIs was reassessed for all patients as follows: 16 of 73 patients showed partial responses (PR, 21.9%); 12 stable diseases (SD, 16.5%); 45 progressive diseases (PD, 61.6%). The disease control rate was 38.4%. AR expression was positive in 24 of 40 specimens (60%). AR-positivity in patients achieving disease control (CR, PR and SD) was not significantly different from that in patients with AR-negativity (p = 0.188). With a median follow-up of 25.4 months (range, 10.5–53.3 months), progression free survival (PFS) was 8.1 weeks in AR-positive and 4 weeks in AR-negative patients (p = 0.025) and overall survival (OS) was significantly longer in patients with AR-positive tumors compared to patients with AR- negative tumors (12.2 vs 4.1 months, p = 0.001). Conclusions: These results suggest that WT EGFR NSCLC patients with AR-positive tumors might have clinical benefit from EGFR-TKIs, indicating AR expression would be another potential marker for the selection of EGFR-TKIs in WT EGFR NSCLC patients. No significant financial relationships to disclose.
Tryptophan metabolism in children with attentional deficit disorder
Authors: M Irwin, K Belendiuk, K McCloskey, D X Freedman
Journal: American Journal of Psychiatry (1981)

The authors present the first report, to their knowledge, of hyperserotonemia in children with attentional deficit disorder who had normal intelligence. Hyperserotonemic children had significantly lower levels of plasma total and protein-bound tryptophan and a higher percentage of free tryptophan than those with normal serotonin levels. Plasma kynurenine did not differ, suggesting that the hyperserotonemia is not due to a blockade of the kynurenine pathway but may reflect on increase in tissue tryptophan uptake and use.
A Controlled Study of Early Neurologic Abnormalities in Men with Asymptomatic Human Immunodeficiency Virus Infection
Authors: Igor J. Koralnik, Anne Beaumanoir, Rudolf Häusler, André Kohler, Avinoam B. Safran, Régine Delacoux, Dominique Vibert, Eugene Mayer, Pierre Burkhard, Albert Nahory, Michel R. Magistris, Joao Sanches, Peter Myers, Fabienne Paccolat, François Quoëx, Victor Gabriel, Luc Perrin, B. Mermillod, Gérard Gauthier, Francis A. Waldvogel, Bernard Hirschel
Journal: New England Journal of Medicine (1990)

Although neurologic complications are frequent in the acquired immunodeficiency syndrome, their incidence and progression in early human immunodeficiency virus (HIV) infection remain controversial. The goal of this study was to assess neurologic manifestations in asymptomatic carriers of HIV.
Case 3-1997
Authors: Scott J. Thaler, Carolyn C. Compton
Journal: New England Journal of Medicine (1997)

Presentation of CaseA 39-year-old man was admitted to the hospital because of acute leukemia.The patient had been well until four weeks earlier, when he began to have progressive malaise, fever, and lymphadenopathy. Epistaxis occurred and required cauterization. Two weeks before admission, the fever resolved, but the lymphadenopathy increased; his gums became painful and bled intermittently. Two days before admission, he lost central vision in the right eye. Hematologic tests were performed (Table 1). He was referred to this hospital.The patient was a computer specialist. There was no history of the use of tobacco, alcohol, or illicit drugs; . . .
Subclinical Renal Response to Streptococcal Infection
Authors: Philip Freedman, H. Peter Meister, Bun Siu Co, A. S. Markowitz, Alvin Dubin
Journal: New England Journal of Medicine (1966)

INVESTIGATORS concerned with the pathogenesis of glomerulonephritis have studied streptococcal infection in man, and its consequences, for many years. Whereas the incidence of rheumatic fever after streptococcal infection has been said to be reasonably constant at approximately 3 per cent,1 the attack rate of acute glomerulonephritis is known to vary considerably. Among the factors considered significant in this variability may be cited the recognized differences in nephritogenic capacity of the many types of beta-hemolytic Group A streptococci, the definitive population under study, the possible influence of early antibiotic therapy and the as yet largely unexplored field of genetic predisposition to . . .
140PD: LUX-Lung 7: A Phase IIb, global, randomised, open-label trial of afatinib vs gefitinib as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations
Authors: K. Park, E.-H. Tan, L. Zhang, V. Hirsh, K. O'Byrne, M. Boyer, J. Yang, T. Mok, M. Kim, L. Paz-Ares
Journal: Journal of Thoracic Oncology (2016)
The Modification of Diet in Renal Disease Study
Authors: S Klahr
Journal: New England Journal of Medicine (1989)

For reasons that are unknown, chronic kidney failure of diverse causes tends to progress to end-stage renal disease. Several hypotheses have been advanced to explain the mechanisms by which renal insufficiency progresses,1 2 3 but none have been definitely established.1 Studies in animals4 and clinical trials in humans5 6 7 with chronic renal disease suggest that the dietary restriction of protein and phosphorus may slow the rate of progression. However, the trials of low-protein, low-phosphorus diets in humans have generally been deficient with respect to experimental design. The deficiencies include the lack of proper randomization procedures, absence or inappropriateness of control populations, use of . . .
Comprehensive molecular characterization of colorectal cancer reveals genomic predictors of immune cell infiltrates.
Authors: Marios Giannakis, Sachet Shukla, Jasmine Xinmeng Mu, Reiko Nishihara, Mai Yamauchi, Yasutaka Sukawa, Zhi Rong Qian, Katsuhiko Nosho, Kentaro Inamura, Samira Bahl, Kimmie Ng, Andrew T. Chan, Jeffrey A. Meyerhardt, Stacey B. Gabriel, Eric Lander, Catherine Wu, Gad Getz, Charles S. Fuchs, Shuji Ogino, Levi A. Garraway
Journal: Journal of Clinical Oncology (2015)

3505 Background: Colorectal cancer (CRC) is a molecularly heterogeneous disease that arises and progresses in the context of a complex microenvironment. Tumor immune cell infiltrates have been shown to be associated with an improved CRC-specific and overall survival. However, the genomic features of CRC that determine the number and types of immune infiltrates remain largely uncharacterized. Methods: We performed Whole Exome Sequencing and microsatellite instability (MSI) analysis on primary CRCs from 689 patients (pts) identified from two large prospective cohorts, the Nurses’ Health Study and the Health Professionals Follow-Up Study. We also immunohistochemically characterized the immune infiltrate (peritumoral, intratumoral periglandular, Crohn’s-like, tumor-infiltrating, and total lymphocyte score) and conducted tissue microarray imaging analysis for T-cell subsets (CD3+, CD8+, CD45RO+, FoxP3+). We utilized a novel computational pipeline to calculate tumor neoantigen load (peptides resulting from somatic mutations and recognized by the immune system as foreign) and subsequently correlated the tumor neoantigen load with the aforementioned immune variables and with pt survival. Results: When compared to microsatellite-stable cancers, MSI-high tumors expressed significantly more neoantigens (P < 2e-16). Tumor neoantigen load significantly correlated with total lymphocytic score in the primary CRCs (P = 4.9e-9) and was most significantly associated with tumor infiltrating lymphocytes (P = 1.6e-15). Among T-cell subsets, tumor neoantigen load was only significantly associated with the CD45RO+ T-cell subset (P = 0.0003). Higher tumor neoantigen load predicted significantly improved CRC-specific and overall survival (P = 0.014 and P = 0.048, respectively). Conclusions: In the large prospective study of molecularly characterized CRCs, tumor neoantigen load predicts greater tumor-infiltrating lymphocytes and memory T-cell infiltration and represents a novel genomic predictor of CRC survival. Our findings link tumor genomics to specific immune response elements and have implications for the therapeutic manipulation of the latter in CRC.
S71 Anti-microbial immune responses in obstructive lung diseases
Authors: F Jaat, S Hasan, C Lanyon, A De Soyza, S Todryk
Journal: Thorax (2015)

<h3>Background</h3> People with chronic lung diseases, such as Bronchiectasis (BE) and smoking-induced Chronic Obstructive Pulmonary Disease (COPD), are susceptible to lung infections which can exacerbate their disease and can be life threatening. A relatively limited range of pathogens cause infections in these conditions and patients suffer repeated infections. It is unclear why such infections do not elicit protective adaptive immune responses. We wish to better understand immune responses against lung-infecting microbes in people with underlying lung disease since immune responses may be connected to disease pathology and also to protection from infection, and may provide a useful marker of colonisation. <h3>Methods</h3> We took peripheral blood samples from 114 BE and 47 COPD patients attending secondary care clinics, and 25 healthy controls, and extracted PBMC and serum. The patients were well-characterised clinically, including their history, aetiology, lung function and longitudinal microbial colonisation. T cell and antibody responses were measured against a panel of common lung-infecting microbial antigens (bacteria, fungi and viruses) using our in-house well-characterised assays (ELISA and ELIspot, respectively). These provided quantitative outputs of specific antibody titre and reactive gamma-interferon-secreting T cells per million PBMC, validated using positive controls. The sputum of patients was cultured, and microbial colonisation defined using prior definitions. Correlations between culture status and bacterial immune responses were analysed. <h3>Results</h3> The predominant pathogens varied between BE and COPD as expected (percentages in Table 1). These included Pseudomonas, Haemophilus influenzae, Streptococcus pneumoniae and Moraxella <i>spp</i>. We found that specific IgG antibody responses correlated with bacterial sputum culture data for Pseudomonas (R = 0.61, p = 0.0001), but not with lung function nor number of exacerbations. In contrast, specific T cell responses did not correlate with microbiology. <h3>Conclusions</h3> Our findings suggest that immune responses measured in the blood against potential lung pathogens contribute minimally to protection from infection or pathology. These tests may however help define colonisation status and could be used as surrogate markers of pathogens in the lung. The poor correlation between T cell responses may be a facet of the disease.
Culture conditions tailored to the cell of origin are critical for maintaining native properties and tumorigenicity of glioma cells
Authors: Pítia F. Ledur, Chong Liu, Hua He, Alexandra R. Harris, Darlan C. Minussi, Hai-Yan Zhou, Mark E. Shaffrey, Ashok Asthagiri, Maria Beatriz S. Lopes, David Schiff, Yi-Cheng Lu, James W. Mandell, Guido Lenz, Hui Zong
Journal: Neuro-Oncology (2016)

Cell culture plays a pivotal role in cancer research. However, culture-induced changes in biological properties of tumor cells profoundly affect research reproducibility and translational potential. Establishing culture conditions tailored to the cancer cell of origin could resolve this problem. For glioma research, it has been previously shown that replacing serum with defined growth factors for neural stem cells (NSCs) greatly improved the retention of gene expression profile and tumorigenicity. However, among all molecular subtypes of glioma, our laboratory and others have previously shown that the oligodendrocyte precursor cell (OPC) rather than the NSC serves as the cell of origin for the proneural subtype, raising questions regarding the suitability of NSC-tailored media for culturing proneural glioma cells. OPC-originated mouse glioma cells were cultured in conditions for normal OPCs or NSCs, respectively, for multiple passages. Gene expression profiles, morphologies, tumorigenicity, and drug responsiveness of cultured cells were examined in comparison with freshly isolated tumor cells. OPC media-cultured glioma cells maintained tumorigenicity, gene expression profiles, and morphologies similar to freshly isolated tumor cells. In contrast, NSC-media cultured glioma cells gradually lost their OPC features and most tumor-initiating ability and acquired heightened sensitivity to temozolomide. To improve experimental reproducibility and translational potential of glioma research, it is important to identify the cell of origin, and subsequently apply this knowledge to establish culture conditions that allow the retention of native properties of tumor cells.
Growth of Normal and Malignant Human Mammary Epithelial Cells in Culture&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: W L Kirkland, N S Yang, T Jorgensen, C Longley, P Furmanski
Journal: JNCI Journal of the National Cancer Institute (1979)

Journal Article Growth of Normal and Malignant Human Mammary Epithelial Cells in Culture Get access Willis L. Kirkland, Willis L. Kirkland Search for other works by this author on: Oxford Academic PubMed Google Scholar Ning-Sun Yang, Ning-Sun Yang Search for other works by this author on: Oxford Academic PubMed Google Scholar Trudy Jorgensen, Trudy Jorgensen Search for other works by this author on: Oxford Academic PubMed Google Scholar Clifford Longley, Clifford Longley Search for other works by this author on: Oxford Academic PubMed Google Scholar Philip Furmanski Philip Furmanski Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 63, Issue 1, July 1979, Pages 29–41, https://doi.org/10.1093/jnci/63.1.29 Published: 01 July 1979 Article history Received: 08 August 1978 Accepted: 02 January 1979 Published: 01 July 1979
Enhancing Effect of a Riboflavin Analog on Azo-Dye Carcinogenesis in Rats
Authors: Ambadas S. Mulay, Roger W. O'Gara
Journal: JNCI Journal of the National Cancer Institute (1968)

Riboflavin analog, U-2112, was added to the laboratory chow diet, with or without N,N-dimethyl-p-phenylazoaniline (DAB), and fed to rats for 4 months. The experiment was terminated 2 months later. Livers of the rats receiving 0.1% U-2112 or 0.12% DAB alone showed no significant changes. Carcinogenic concentration (0.18%) of DAB combined with even 0.01% U-2112 was too toxic. Subcarcinogenic dose (0.12%) of DAB with 0.1% U-2112 for the first 2 weeks and 0.05% for the rest of the time produced cholangiofibrosis of the liver of most of the rats and hepatomas in 40% of the animals.
Soundings: Doing simple things well
Authors: Trisha Greenhalgh
Journal: BMJ (2003)

Spouse has a new gadget. I warned him that if he didn't let up about it I'd write about it in this column.

The main box of tricks is about the size of a paperback book. Its purpose is to predict the weather. Several subsidiary devices, each the size of a matchbox, have been fixed to the outside wall of our house. They transmit a continuous stream of data on temperature, humidity, wind speed, and the like to the central processing unit, prompting unsolicited announcements such as “Did you know it's three degrees colder on the patio than it is outside the loo window?”

Initially, I thought that the gadget was a triumph of marketing over performance. Surely no one in their right mind would spend a three figure sum on something that provides little more information than you could get from a thermometer, a pine cone, and a bit of spit on the end of your finger?

But I have to admit that I've come round to it. Sure, the data collected by the gadget are spectacularly unsophisticated. Indeed, part of its elegance is that its inputs are commonplace and easily understood. It depicts the disparate data streams on an easy-to-read graph, compares them with control parameters, and presents information on the rate and direction of change in a way that directly informs practical decision making. The barometric pressure on my front porch is currently 998 millibars. No big deal. But get this—that's the lowest value recorded all month; it has been falling steadily for three days; and there has been a corresponding fall in temperature and rise in humidity. You've probably concluded that I should take an umbrella when I go out. And in case you didn't get there, a little pre-programmed icon is already flashing this very message.

Medical workload in every specialty is moving relentlessly from a cure model to a risk management model. A generation ago Julian Tudor Hart described general practice as “doing simple things well, for large numbers of people, few of whom feel ill.” Perhaps we should now paraphrase this to “collecting standard data frequently and faithfully; entering them (consistently coded) into a computer that can integrate them across body systems and time; and responding promptly to any reminders generated by the decision support system.”
Skp2, a prognostic marker and potential therapeutic target in metastatic melanoma
Authors: G. Wang, D. Hanniford, A. Rose, A. Gaziel, A. Pavlick, X. Zhou, J. Wang, M. Pagano, E. Hernando, I. Osman
Journal: Journal of Clinical Oncology (2009)

11034 Background: Skp2, a known oncogene, is overexpressed in several types of tumors and is associated with worse recurrence rate and overall survival in primary melanoma patients. Moreover, the anti-proliferative effects of Skp2 siRNA on various tumor cell lines have prompted the preclinical testing of Skp2 small molecule inhibitors. In this study, we assessed the clinical relevance and molecular mechanism(s) underlying Skp2 overexpression in metastatic melanoma patients. Methods: Skp2 protein levels were measured in 122 metastatic melanoma specimens using immunohistochemistry (IHC), and the association between Skp2 overexpression and post-recurrence survival was examined. Moreover, 22 cell lines (2 normal primary melanocytes, 2 primary immortal melanocytes, 4 primary melanoma cell lines, and 18 metastatic melanoma cell lines) were evaluated for Skp2 genomic amplification using Single Nucleotide Polymorphism (SNP) arrays (Affymetrix 6.0) and Skp2 gene expression using mRNA arrays (Affymetrix U133A 2.0) and quantitative RT-PCR. We also screened 18 cell lines for Skp2 mutation by sequencing. Results: Skp2 overexpression, defined as &gt;25% tumor cells, was associated with shorter 3-yr post-recurrence survival (37%) compared to Skp2 expression ≤25% (55%) (HR=1.89, 95%, CI= 1.04, 3.42, p=0.04). Skp2 overexpression was significantly associated with the site of melanoma metastasis: visceral (n= 12; 89%), lymph node (n=49; 36%), brain (n=15; 14%), and soft-tissue (n=36; 6%) (p&lt;0.001). SNP array revealed genomic amplification at the Skp2 locus in 6 (33%) metastatic cell lines and one primary melanoma cell line. Skp2 genomic amplification was associated with increased transcript expression. No Skp2 mutations were identified. Conclusions: Skp2 protein overexpression is associated with worse prognosis in metastasis in melanoma. Our results also support that gene amplification, rather than a Skp2 gene mutation, may be the major mechanism responsible for Skp2 aberrant expression in metastatic melanoma. No significant financial relationships to disclose.