tbuckley/cabot-search huggingface dataset:
Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma
Authors: Michael A. Davies, Katherine Stemke-Hale, E. Lin, Carmen Tellez, Wanleng Deng, Yennu N. Gopal, Scott E. Woodman, Tiffany C. Calderone, Zhenlin Ju, Alexander J. Lazar, Victor G. Prieto, Kenneth Aldape, Gordon B. Mills, Jeffrey E. Gershenwald
Journal: Clinical Cancer Research (2009)

PURPOSE: Activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway has been implicated in melanoma based primarily on the prevalence of mutations in PTEN and NRAS. To improve our understanding of the regulation and clinical significance of the PI3K-AKT pathway in melanoma, we quantitatively measured the levels of phosphorylated AKT, its substrate GSK3alpha/beta, and its negative regulator PTEN in clinical metastases. Results were compared with mutational status, clinical outcomes, and sites of metastasis. EXPERIMENTAL DESIGN: DNA and protein were isolated from dissected frozen melanoma metastases (n = 96). Activating mutations of BRAF, NRAS, AKT, PIK3CA, and KIT were detected by mass spectroscopy genotyping. Phosphorylated AKT (Ser473 and Thr308), P-GSK3alpha/beta, and PTEN protein expression were measured by reverse-phase protein array. A panel of human melanoma cells lines (n = 58) was analyzed for comparison. RESULTS: BRAF-mutant tumors had higher levels of P-AKT-Ser473 (P = 0.01), P-AKT-Thr308 (P = 0.002), and P-GSK3alpha/beta (P = 0.08) than NRAS-mutant tumors. Analysis of individual tumors showed that almost all tumors with elevated P-AKT had low PTEN levels; NRAS-mutant tumors had normal PTEN and lower P-AKT. Similar results were observed in melanoma cell lines. Stage III melanoma patients did not differ in overall survival based on activation status of the PI3K-AKT pathway. Brain metastases had significantly higher P-AKT and lower PTEN than lung or liver metastases. CONCLUSIONS: Quantitative interrogation of the PI3K-AKT pathway in melanoma reveals unexpected significant differences in AKT activation by NRAS mutation and PTEN loss, and hyperactivation of AKT in brain metastases. These findings have implications for the rational development of targeted therapy for this disease. (Clin Cancer Res 2009;15(24):7538-46).
The biochemical aftermath of anti-amyloid immunotherapy
Authors: Chera L Maarouf, Ian D Daugs, Tyler A Kokjohn, Walter M Kalback, R Lyle Patton, Dean C Luehrs, Eliezer Masliah, James AR Nicoll, Marwan N Sabbagh, Thomas G Beach, Eduardo M Castaño, Alex E Roher
Journal: Molecular Neurodegeneration (2010)

Active and passive immunotherapy in both amyloid-beta precursor protein (APP) transgenic mice and Alzheimer's Disease (AD) patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the Aβ peptide 1-42 (AN-1792) and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC) cases.All patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of Aβ species remnants by ELISA suggested that total Aβ levels may have been reduced, although because the amounts of Aβ peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric Aβ peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of Aβ-related peptides, some of them with elongated C-terminal sequences. Pro-inflammatory TNF-α levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non-immunized AD groups.Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques by AN-1792 was impressive, proportionate alterations in the clinical progression of AD were not evident. The fact that plaque elimination did not alter the trajectory of decline into dementia suggests the likelihood that these deposits alone are not the underlying cause of dementia.
Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial
Authors: David H Miller, Thomas Weber, Richard Grove, Claire Wardell, Joseph Horrigan, Ole Graff, Gillian Atkinson, Pinky Dua, Tarek Yousry, David MacManus, Xavier Montalban
Journal: The Lancet Neurology (2012)
Milatuzumab-Conjugated Liposomes as Targeted Dexamethasone Carriers for Therapeutic Delivery in CD74+ B-cell Malignancies
Authors: Yicheng Mao, Georgia Triantafillou, Erin Hertlein, William Towns, Matthew Stefanovski, Xiaokui Mo, David Jarjoura, Mitch Phelps, Guido Marcucci, Ly James Lee, David M. Goldenberg, Robert J. Lee, John C. Byrd, Natarajan Muthusamy
Journal: Clinical Cancer Research (2012)

Corticosteroids are widely used for the treatment of B-cell malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia; however, this class of drug is associated with undesirable off-target effects. Herein, we developed novel milatuzumab-conjugated liposomes as a targeted dexamethasone carrier for therapeutic delivery in CD74(+) B-cell malignancies and explored its effect against the disease.
Frequency and risk factors for prevalent, incident, and persistent genital carcinogenic human papillomavirus infection in sexually active women: community based cohort study
Authors: P. Oakeshott, A. Aghaizu, F. Reid, R. Howell-Jones, P. E. Hay, S. T. Sadiq, C. J. Lacey, S. Beddows, K. Soldan
Journal: BMJ (2012)

<b>Objective</b> To investigate frequency and risk factors for prevalent, incident, and persistent carcinogenic human papillomavirus (HPV) in young women before the introduction of immunisation against HPV types 16 and 18 for schoolgirls. <b>Design</b> Cohort study <b>Setting</b> 20 London universities and further education colleges. <b>Participants</b> 2185 sexually active female students, mean age 21 years (range 16-27), 38% from ethnic minorities, who took part in the POPI (prevention of pelvic infection) chlamydia screening trial in 2004-08 and who provided duplicate, self taken vaginal swabs and completed questionnaires at baseline. At follow-up, a median of 16 months later, 821 women (38%) returned repeat vaginal swabs by post. In 2009-10, stored samples were tested for HPV. <b>Results</b> Samples from 404/2185 (18.5% (95% CI 16.9% to 20.2%)) of the cohort were positive for carcinogenic HPV at baseline, including 15.0% (327) positive for non-vaccine carcinogenic genotypes. Reporting two or more sexual partners in the previous year and concurrent <i>Chlamydia trachomatis </i>or bacterial vaginosis were independent risk factors for prevalent vaginal HPV infection. Infection with one or more new HPV types was found in 17.7% (145/821) of follow-up samples, giving an estimated annual incidence of carcinogenic HPV infection of 12.9% (95% CI 11.0% to 15.0%). Incident infection was more common in women reporting two or more partners in the previous year, aged&lt;20, of black ethnicity, or with <i>C trachomatis</i> vaginosis at baseline. Multiple partners was the only independent risk factor for incident infection (adjusted relative risk 1.99 (95% CI 1.46 to 2.72)). Of 143 women with baseline carcinogenic HPV infection, 20 (14% (8.3% to 19.7%) had infection with the same carcinogenic HPV type(s) detected after 12-28 months. Of these women, 13 (65%) had redetected infection with HPV 16 or 18, and nine (45%) with non-vaccine carcinogenic HPV genotypes. <b>Conclusion</b> In the first UK cohort study of carcinogenic HPV in young women in the community, multiple sexual partners was an independent predictor of both prevalent and incident infection. Infection with non-vaccine carcinogenic genotypes was common. Although current HPV vaccines offer partial cross protection against some non-vaccine carcinogenic HPV types, immunised women will still need cervical screening.
DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4
Authors: M Bardini, R Spinelli, S Bungaro, E Mangano, L Corral, I Cifola, G Fazio, M Giordan, G Basso, G De Rossi, A Biondi, C Battaglia, G Cazzaniga
Journal: Leukemia (2009)
The international normalized ratio calibrated for cirrhosis (INRliver) normalizes prothrombin time results for model for end-stage liver disease calculation
Authors: Armando Tripodi, Veena Chantarangkul, Massimo Primignani, Federica Fabris, Alessandra Dell'Era, Cinzia Sei, Pier Mannuccio Mannucci
Journal: Hepatology (2007)

The model for end-stage-liver-disease (MELD) is a mathematical score used to prioritize patients for liver transplantation and includes results for creatinine, bilirubin, and prothrombin time (PT) expressed as international normalized ratio (INR). The rationale of using the MELD rests on the assumption that the score would be the same across the country if the methods used to measure the variables yield the same numerical results regardless of the testing laboratory. Evidence was provided that specific methodologies may influence the MELD, and the PT-INR was identified as the most important. This study was designed to provide information on the between-thromboplastin variability and to explore alternatives to obviate such variability. Fifty-seven patients with cirrhosis were selected, and their PTs were measured with 7 thromboplastins. The thromboplastins were previously calibrated by testing plasmas from patients on vitamin K antagonists and healthy subjects to assign the international sensitivity index (ISI(vka)) needed to convert PT into INR. Each of the thromboplastins was also assigned an ISI(liver) by substituting in the calibration the plasmas from vitamin K antagonist patients with plasmas from patients with cirrhosis. INR and MELD values for individual patients were calculated by using the ISI(vka) or the ISI(liver). The mean INR(vka) obtained with the 7 thromboplastins were significantly different (P < 0.001). Conversely, the mean INR(liver) were not. Similarly, the mean MELD(vka) were significantly different (P < 0.001), but those differences were abrogated for the MELD(liver).The alternative thromboplastin calibration using plasmas from patients with cirrhosis instead of from vitamin K antagonist patients is feasible and may resolve the variability of the MELD to prioritize patients for transplantation.
Intracardiac ectopic thyroid: a case report and review of published cases.
Authors: I Richmond, J S Whittaker, A K Deiraniya, R Hassan
Journal: Thorax (1990)

A woman with ectopic intracardiac thyroid tissue showing features of a colloid storage goitre presented with ventricular tachycardias and signs of right ventricular outflow obstruction. As the tumour was benign and removed at necropsy, the results of surgery are likely to have been good, but she died from a cardiac arrest before operation.
Assuring the Health of Immigrants: What the Leading Health Indicators Tell Us
Authors: Namratha R. Kandula, Margaret Kersey, Nicole Lurie
Journal: Annual Review of Public Health (2004)

Over the past 20 years, the United States has experienced one of the largest waves of immigration in its history. Understanding the health status and needs of immigrants is important because of their growing numbers and their contribution to the health of the nation, but it is challenging because of gaps in national databases, the heterogeneity of immigrant populations, and uncertainty about how migration affects health. Healthy People 2010 outlines the nation's public health objectives for the current decade. It includes ten leading health indicators (LHIs) chosen because of their importance as public health issues, their ability to motivate action, and the availability of data to measure their progress. In this paper, we discuss the health of immigrants from the perspective of these LHIs, as they provide a framework for anticipating some of the future health needs of immigrants and help define priority areas for research and action.
Topographical transcriptome mapping of the mouse medial ganglionic eminence by spatially resolved RNA-seq
Authors: Sabrina Zechel, Pawel Zajac, Peter Lönnerberg, Carlos F Ibáñez, Sten Linnarsson
Journal: Genome biology (2014)

Cortical interneurons originating from the medial ganglionic eminence, MGE, are among the most diverse cells within the CNS. Different pools of proliferating progenitor cells are thought to exist in the ventricular zone of the MGE, but whether the underlying subventricular and mantle regions of the MGE are spatially patterned has not yet been addressed. Here, we combined laser-capture microdissection and multiplex RNA-sequencing to map the transcriptome of MGE cells at a spatial resolution of 50 μm. Distinct groups of progenitor cells showing different stages of interneuron maturation are identified and topographically mapped based on their genome-wide transcriptional pattern. Although proliferating potential decreased rather abruptly outside the ventricular zone, a ventro-lateral gradient of increasing migratory capacity was identified, revealing heterogeneous cell populations within this neurogenic structure. We demonstrate that spatially resolved RNA-seq is ideally suited for high resolution topographical mapping of genome-wide gene expression in heterogeneous anatomical structures such as the mammalian central nervous system.
Effects of the Hepatocarcinogen 2-Acetylaminofluorene on Insulin Binding to Microsomal and Golgi Fractions of Rat Liver Cells2
Authors: Arye Lev-Ran, Zeev Josefsberg, Brian I. Carr, Gegham Barseghian, David Hwang
Journal: JNCI Journal of the National Cancer Institute (1984)

Adult male Fischer rats fed the hepatocarcinogen 2-acetylaminofluorene [(2-AAF) CAS: 53-96-3; N-fluoren-2-yl-aceta-mide] at 0.02% showed a sharp decrease in the insulin binding to the Golgi fraction of the liver cells: from 10.0% specific binding per 0.1 mg protein in control animals to 5.9% after only 2 days and to 1.5% after 21 days of feeding 2-AAF. A less pronounced and slower decrease was observed in the microsomal fraction: from 19.1% specific binding per 0.5 mg protein in controls to a nadir of 10.8% after 46 days. The low binding of insulin to both fractions was observed for the 85 days of the experiment and persisted also in the animals fed 2-AAF for 90–107 days and then taken off the carcinogen for 30–75 days. The decrease in binding was due to the apparent decrease in the number of receptors. Neither 2-AAF nor its metabolites N-hydroxy-2-AAF (CAS: 53-95-2; N-fluoren-2-yl-acetohydroxamic acid) and N-acetoxy-2-AAF (CAS: 6098-44-8; N,O-diacetyl-N-fluoren-2-yl-hydroxylamine) influenced the insulin binding to the microsomes when added to the reaction mixture in vitro.
The "Right to Know": Toxics Information Transfer in the Workplace
Authors: N A Ashford, C C Caldart
Journal: Annual Review of Public Health (1985)

The transfer of information regarding workplace exposure to toxic substances has received considerable public attention. It is clear that workers need an accurate picture of the nature and extent of likely chemical exposures in order to decide whether to enter or remain in a particular workplace. Workers also need to have  ledge regarding past or current exposures in order to be alert to the onset of occupational disease. Regulatory agencies must have timely access to such information if they are to devise effective strategies to reduce disease and death from occupational exposures to toxic substances. Accordingly, laws designed to step up this flow of information have recently been promulgated at the federal, state, and local levels. Indeed, the right to know has become a political battleground in many states and communities, and has been the subject of intensive organizing efforts by business, labor, and citizen-action groups. Not surprisingly, this flurry of political activity has generated a degree of confusion. What is meant by the right to know? Who has the right? How is it exercised? What information is within its scope? These questions touch on a relatively complicated area of the law, and their resolution demands attention to the specific provisions of a number of different statutes, ordinances, and regulations. But this is also an area of the law that is amenable to a relatively simple conceptual framework. The purpose of this article is to lay out that framework in practical terms. In addition, we offer a general road map through the current body of law governing toxics information transfer in the workplace. (See Ref. 2 for a more detailed discussion of the issues raised here.)
Epidermal Growth Factor Receptor Variant III Status Defines Clinically Distinct Subtypes of Glioblastoma
Authors: Christopher E. Pelloski, Karla V. Ballman, Alfred F. Furth, Li Zhang, E. Lin, Erik P. Sulman, Krishna Bhat, J. Matthew McDonald, W.K. Alfred Yung, Howard Colman, Shiao Y. Woo, Amy B. Heimberger, Dima Suki, Michael D. Prados, Susan M. Chang, Fred G. Barker, Jan C. Buckner, C. David James, Kenneth Aldape
Journal: Journal of Clinical Oncology (2007)

The clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression in glioblastoma multiforme (GBM) and its relationship with other key molecular markers are not clear. We sought to evaluate the clinical significance of GBM subtypes as defined by EGFRvIII status.The expression of EGFRvIII was assessed by immunohistochemistry in 649 patients with newly diagnosed GBM. These data were then examined in conjunction with the expression of phospho-intermediates (in a subset of these patients) of downstream AKT and Ras pathways and YKL-40 as well as with known clinical risk factors, including the Radiation Therapy Oncology Group's recursive partitioning analysis (RTOG-RPA) class.The RTOG-RPA class was highly predictive of survival in EGFRvIII-negative patients but much less predictive in EGFRvIII-positive patients. These findings were seen in both an initial test set (n = 268) and a larger validation set (n = 381). Similarly, activation of the AKT/MAPK pathways and YKL-40 positivity were predictive of poor outcome in EGFRvIII-negative patients but not in EGFRvIII-positive patients. Pair-wise combinations of markers identified EGFRvIII and YKL-40 as prognostically important. In particular, outcome in patients with EGFRvIII-negative/YKL-40-negative tumors was significantly better than the outcome in patients with the other three combinations of these two markers.Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.
Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients
Authors: Dieter Worlitzsch, Robert Tarran, Martina Ulrich, Ute Schwab, Aynur Cekici, Keith C. Meyer, Peter Birrer, Gabriel Bellon, Jürgen Berger, Tilo Weiss, Konrad Botzenhart, James R. Yankaskas, Scott Randell, Richard C. Boucher, Gerd Döring
Journal: Journal of Clinical Investigation (2002)

Current theories of CF pathogenesis predict different predisposing “local environmental” conditions and sites of bacterial infection within CF airways. Here we show that, in CF patients with established lung disease, Psuedomonas aeruginosa was located within hypoxic mucopurulent masses in airway lumens. In vitro studies revealed that CF-specific increases in epithelial O2 consumption, linked to increased airway surface liquid (ASL) volume absorption and mucus stasis, generated steep hypoxic gradients within thickened mucus on CF epithelial surfaces prior to infection. Motile P. aeruginosa deposited on CF airway surfaces penetrated into hypoxic mucus zones and responded to this environment with increased alginate production. With P. aeruginosa growth in oxygen restricted environments, local hypoxia was exacerbated and frank anaerobiosis, as detected in vivo, resulted. These studies indicate that novel therapies for CF include removal of hypoxic mucus plaques and antibiotics effective against P. aeruginosa adapted to anaerobic environments.
Reversible alterations in excitation-contraction coupling during myocardial hypertrophy in rat papillary muscle.
Authors: J M Capasso, R S Aronson, E H Sonnenblick
Journal: Circulation Research (1982)

To investigate the possible role of an alteration in excitation-contraction coupling in cardiac hypertrophy, we compared simultaneously recorded action potentials along with isometric or isotonic contractions of normal and hypertrophied papillary muscles. Hypertrophy was produced by renal hypertension in rats. Hypertrophied papillary muscles were taken from rats that had been hypertensive for 10 [HBP (10)] or 20 [HBP (20)] weeks. Regression of changes induced by hypertrophy was studied in rats that had been hypertensive for 10 weeks and then made normotensive for 10 weeks by removal of the ischemic kidney. Papillary muscles from age-matched, sham-operated rats [SHAM (10), SHAM (20)] were used as controls. We found that HBP (10) rats had significantly longer action potentials than SHAM (10) rats and that difference in the action potential duration recorded during isotonic and isometric contractions was significantly different from SHAM (10) and HBP (10) rats. Peak developed tension was the same in HBP (10) and SHAM (10) muscles, but the duration of isometric contraction and time-to-peak shortening were longer in HBP (10) muscles. Similarly, whereas the peak tension was the same in HBP (20) and SHAM (20) muscles, the duration of the action potential and isometric contraction, as well as the time-to-peak tension, was longer in HBP (20) muscles. The longer values for action potential duration, isometric contraction, and time-to-peak tension in HBP (20) muscles returned to SHAM values in HBP (R) muscles. The functional relationship between contraction and the action potential time course was assessed by plotting action potential duration against four parameters of contraction: peak developed tension, time-to-peak tension, time-to-half relaxation, and time-to-peak shortening. Statistical analysis of these data showed a significant correlation between action potential duration and all four parameters of contraction in SHAM (10) and SHAM (20) muscles. In contrast, HBP (10) muscles showed a significant correlation between action potential duration and only two contractile parameters, whereas action potential duration did not correlate significantly with any of the contractile parameters in HBP (20) muscles. Remarkably, in HBP (R) preparations a significant correlation was restored between action potential duration and three of the four contractile parameters. The results of this study suggest that reversible cardiac hypertrophy is associated with reversible alterations in excitation-contraction coupling. The reversibility of the mechanical and electrical alterations that accompany hypertrophy suggests, in turn, that cardiac hypertrophy is an adaptive process.