tbuckley/cabot-search huggingface dataset:
SV40 T/t-Common Polypeptide Specifically Induces Apoptosis in Human Cancer Cells that Overexpress HER2/neu
Authors: Chun-Chiang Wen, Shih-An Cheng, Shu-Ping Hsuen, Ya-Ling Huang, Zong-Keng Kuo, Hsin-Fang Lee, Chou-Hua Kuo, Jia-Ling Du, Won-Bo Wang
Journal: Cancer Research (2006)

Abstract Previously, we reported that SV40 T/t-common polypeptide, which contains the NH2-terminal common domain of SV40 large T and small t antigens, can repress HER2/neu (also known as erbB-2) expression and consequently suppress the tumorigenic potential of the HER2/neu-overexpressing ovarian carcinoma cells. Here we report that T/t-common could specifically induce apoptosis in HER2/neu-overexpressing human cancer cell lines but not in nontransformed cell lines and HER2/neu low-expressing human cancer cell lines. The ability of T/t-common to induce apoptosis in HER2/neu-overexpressing cancer cells was derived from its ability to inhibit HER2/neu because reexpression of a large amount of HER2/neu could block apoptosis induced by T/t-common. T/t-common expression in HER2/neu-overexpressing SK-OV-3 cancer cells led to down-regulation of Bcl-2 and Bcl-XL, and overexpression of Bcl-2 could inhibit the ability of T/t-common to induce apoptosis in these cells. Therefore, the apoptosis-inducing activity of T/t-common is related to its ability to inhibit Bcl-2 expression in HER2/neu-overexpressing cancer cells. Consistent with the apoptosis-inducing activity of T/t-common, we found that T/t-common could specifically inhibit the soft-agarose colony-forming ability of the HER2/neu-overexpressing human cancer cell lines but not that of the HER2/neu low-expressing human cancer cell lines. Finally, we showed that T/t-common could specifically sensitize HER2/neu-overexpressing human cancer cell lines, but not HER2/neu low-expressing human cancer cell lines, to chemotherapeutic agent etoposide. Together, these data suggest that T/t-common alone or in combination with chemotherapy may provide a new approach for treatment of cancers that overexpress HER2/neu. (Cancer Res 2006; 66(11): 5847-57)
Nitric oxide, hypoxia, and superoxide: the good, the bad, and the ugly!
Authors: R A Dweik
Journal: Thorax (2005)

A possible role for NO in ARDS

Nitric oxide (NO) is endogenously synthesised by nitric oxide synthases (NOS) which convert l-arginine to l-citrulline and NO. Three NOS isoforms (types I, II and III) have been identified and all of them are expressed in the human lung.1–8 NOS I (nNOS) and III (eNOS) are constitutively expressed in tissues and are dependent on increases in intracellular calcium for enzyme activation while NOS II (iNOS) is an inducible form that is calcium independent (table 1).9 All NOS isoforms require oxygen, NADPH, FAD, FMN, tetrahydrobiopterin, and calmodulin for activity.1,9 NO is recognised to have a key role in virtually all aspects of lung biology and has been implicated in the pathophysiology of lung diseases.1,4,6,10–15 It is involved in pulmonary neurotransmission, host defence and bacteriostasis, airway and vascular smooth muscle relaxation, pulmonary capillary leak, inflammation, mucociliary clearance, airway mucus secretion, and cytotoxicity.4,6,14

View this table:

 Table 1  
 Nitric oxide synthase enzymes



Cellular sources of NO in the lung include epithelial cells, endothelial cells of pulmonary arteries and veins, inhibitory non-adrenergic non-cholinergic neurones, smooth muscle cells, mast cells, mesothelial cells, fibroblasts, neutrophils, lymphocytes, and macrophages.4,6,14 Specifically, NOS I is located in inhibitory non-adrenergic non-cholinergic neurones in the lung while NOS III is found in endothelial cells and the brush border of ciliated epithelial cells.1,5,7 NOS II is found in the epithelial cells of the airway. Although NOS II may be induced in several types of cells in response to cytokines, endotoxin, or reactive oxygen species, it is continuously expressed in normal human airway epithelium at basal airway conditions.8,16

Once produced, NO is freely diffusible and enters target cells activating soluble guanylate cyclase to produce guanosine 3′,5′-cyclic monophosphate (cGMP) …
Inhibition of woodchuck hepatitis virus replication by adenine arabinoside monophosphate coupled to lactosaminated poly-L-lysine and administered by intramuscular route
Authors: Luigi Fiume, Giuseppina Di Stefano, Corrado Busi, Alessandro Mattioli, Maria Rapicetta, Roberto Giuseppetti, Anna Rita Ciccaglione, Claudio Argentini
Journal: Hepatology (1995)

We prepared a hepatotropic conjugate, suitable for intramuscular (IM) injection, of lactosaminated poly-Llysine with adenine arabinoside monophosphate (ara-AMP), a drug active against hepatitis B virus (HBV). We studied its organ distribution in mice and its antiviral activity in woodchucks that are carriers of woodchuck hepatitis virus (WHV). In mice, after IM administration of a conjugate tritiated in the drug moiety (5.2 μg/g equal to 2 μg/g of ara-AMP) radioactivity in liver was three times greater than in kidney, spleen, and intestine. On the contrary, after IM injection of unconjugated, tritiated, are-AMP (5 μg/g) the amounts of radioactivity in liver, spleen, and kidney were similar. Unconjugated ara-AMP and the conjugate were administered IM to woodchucks for 13 days. Unconjugated ara-AMP decreased viremia at the daily dose of 5 mg/kg but was ineffective at 2.5 mg/kg. The conjugate at the daily doses of 4.2 and 7 mg/kg (equal to 1.5 and 2.5 mg/kg of ara-AMP, respectively) markedly lowered the viremia, which decreased to undetectable levels in the animals treated with the higher dose. Assuming that in HBV-infected patients the same doses will be active, then the amount of conjugate (soluble at 200 mg/mL) required by a 70-kg patient will be contained in a volume of 1.5 to 2.5 mL, compatible with the IM route. Compared with a similar ara-AMP complex with lactosaminated human albumin, currently being studied in clinical trials for the treatment of chronic type B hepatitis, which must be infused intravenously, the present conjugate might provide more patient compliance because of IM administration. (HEPATOLOGY 1995; 22:1072–1077.).
Expansion of Hexose Transporter Genes Was Associated with the Evolution of Aerobic Fermentation in Yeasts
Authors: Z. Lin, W.-H. Li
Journal: Molecular Biology and Evolution (2010)

The genetic basis of organisms' adaptation to different environments is a central issue of molecular evolution. The budding yeast Saccharomyces cerevisiae and its relatives predominantly ferment glucose into ethanol even in the presence of oxygen. This was suggested to be an adaptation to glucose-rich habitats, but the underlying genetic basis of the evolution of aerobic fermentation remains unclear. In S. cerevisiae, the first step of glucose metabolism is transporting glucose across the plasma membrane, which is carried out by hexose transporter proteins. Although several studies have recognized that the rate of glucose uptake can affect how glucose is metabolized, the role of HXT genes in the evolution of aerobic fermentation has not been fully explored. In this study, we identified all members of the HXT gene family in 23 fully sequenced fungal genomes, reconstructed their evolutionary history to pinpoint gene gain and loss events, and evaluated their adaptive significance in the evolution of aerobic fermentation. We found that the HXT genes have been extensively amplified in the two fungal lineages that have independently evolved aerobic fermentation. In contrast, reduction of the number of HXT genes has occurred in aerobic respiratory species. Our study reveals a strong positive correlation between the copy number of HXT genes and the strength of aerobic fermentation, suggesting that HXT gene expansion has facilitated the evolution of aerobic fermentation.
Prognostic Factors for Survival in Patients With Inoperable Lung Cancer&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: K E Stanley
Journal: JNCI Journal of the National Cancer Institute (1980)

Seventy-seven prognostic factors were considered in an evaluation of more than 5,000 patients with inoperable bronchogenic carcinoma of the lung; these patients were entered on the Veterans Administration Lung Group protocols 9-15 (1968-78). Fifty prognostic factors for survival were identified, and their relative contributions to patient survival were considered. The three most important prognostic factors affecting survival were the Karnofsky initial performance status score, extent of disease, and weight loss in the previous 6 months. These factors denoted three general prognostic components: current physical status, current disease status, and prior physical status. Initial performance status was the dominant prognostic factor. Characterization of patient's function status with the use of the Karnofsky scale was preferred to a summarized scale or a dichotomization into ambulatory versus nonambulatory. The current practice of dichotomizing factors resulted in the loss of much prognostic information. Other factors, such as tumor size, histologic type, and institution, appeared to be important when considered alone. However, their contribution was relatively minor after a correction was made for the effects of initial performance status, extent of disease, and prior weight loss. Depending on these three prognostic factors alone, median survival varied between 6 weeks and over a year. Reporting of results without the consideration of such prognostic factors severly hampers any comparisons that may be made between investigations.
Depressive State- and Disease-Related Alterations in Neural Responses to Affective and Executive Challenges in Geriatric Depression
Authors: Lihong Wang, K. Ranga Krishnan, David C. Steffens, Guy G. Potter, Florin Dolcos, Gregory McCarthy
Journal: American Journal of Psychiatry (2008)

Geriatric depression has been associated with a heterogeneous neuropathology. Identifying both depressive state-related and disease-related alterations in brain regions associated with emotion and cognitive function could provide useful diagnostic information in geriatric depression.Twelve late-onset acutely depressed patients, 15 patients fully remitted from major depression, and 20 healthy comparison subjects underwent event-related functional MRI. Brain activation and deactivation associated with executive and emotional processing were investigated using an emotional oddball task in which circles were presented infrequently as attentional targets and sad and neutral pictures as novel distractors.Significant changes in brain activation in patients were found mainly in response to attentional targets rather than to sad distractors. Relative to healthy comparison subjects, the depressed patients had attenuated activation in the regions of the executive system, including the right middle frontal gyrus, the cingulate, and inferior parietal areas. Activity in the middle frontal gyrus revealed depressive state-dependent modulation, whereas attenuated activation in the anterior portion of the posterior cingulate and inferior parietal regions persisted in the remitted subjects, suggesting a disease-related alteration. Enhanced deactivation was observed in the posterior portion of the posterior cingulate, which was also state dependent. The remitted group did not show this deactivation.Our results indicate distinct roles for the right middle frontal gyrus and the anterior and posterior portions of the posterior cingulate cortex in geriatric depression. The deactivation of the posterior portion of the posterior cingulate could be informative for differentiation of cognitive dysfunction related to depression from other conditions, such as mild cognitive impairment.
Alternate ventriculoatrial Wenckebach conduction.
Authors: S Levy, R Roudaut, E Bouvier, I W Obel, J Clementy, H Bricaud
Journal: Circulation (1980)

Three cases are presented showing retrograde alternate Wenckebach periods. Retrograde alternate Wenckebach periods were defined as 2:1 ventriculoatrial (VA) block in which the conducted beats showed progressive prolongation of conduction (VA) time. The sequence terminates with two or three successively blocked ventricular beats. In one of the three cases the level of block was identified as being in the atrioventricular (AV) node. In the other two the level of block could not be clearly identified. This report provides further evidence for the concept of multilevel block within the AV node. Retrograde alternate Wenckebach periods may explain some instances of variation of atrial depolarization intervals during episodes of ventricular tachycardia and may be clinically significant.
Relative Ability of Full and Partial Forced Expiratory Maneuvers to Identify Diminished Airway Function in Infants with Cystic Fibrosis
Authors: Sarath C. Ranganathan, Andrew Bush, Carol Dezateux, Siobhán B. Carr, Ah-Fong Hoo, Sooky Lum, Su Madge, John Price, John Stroobant, Angie Wade, Colin Wallis, Hilary Wyatt, Janet Stocks
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

The tidal and raised volume rapid thoracoabdominal compression techniques are increasingly used to detect diminished airway function in infancy. The aim of this study was to assess the relative ability of parameters measured by these techniques to identify diminished airway function in infants newly diagnosed with cystic fibrosis (CF) with and without clinical evidence of prior lower respiratory illness. A cross-sectional, prospective study design was used in which maximal flow at functional residual capacity (VmaxFRC) from the tidal technique and FVC, FEV0.5, FEF75, and FEF25–75 from the raised volume technique were measured in 47 infants with CF and 187 healthy infants of similar body size, sex distribution, ethnic group, and exposure to maternal smoking. Multiple linear regression was used to assess group differences and to calculate SD scores for each parameter for the infants with CF. Airway function was also compared with clinical assessments of respiratory status made by pediatric pulmonologists. FEV0.5 was significantly diminished in 13 infants with CF, of whom 4 had been identified by clinicians as having normal respiratory status. Only one infant with CF had a VmaxFRC below the estimated normal range. Airway function is diminished in infants with CF irrespective of prior lower respiratory illness and in those whose respiratory status is considered normal by pediatric pulmonologists. In infants with CF, the raised volume technique identified diminished airway function more frequently than the tidal technique.
A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oral γ-Secretase Inhibitor PF-03084014
Authors: Wells A. Messersmith, Geoffrey I. Shapiro, James M. Cleary, Antonio Jimeno, Arvind Dasari, Bo Huang, M. Naveed Shaik, Rossano Cesari, Xianxian Zheng, Jennifer M. Reynolds, Patricia A. English, Karen R. McLachlan, Kenneth A. Kern, Patricia M. LoRusso
Journal: Clinical Cancer Research (2014)

To estimate the maximum tolerated dose (MTD) for continuous oral administration of the γ-secretase inhibitor PF-03084014, determine the recommended phase II dose (RP2D), and evaluate safety and preliminary activity in patients with advanced solid tumors.This open-label, phase I study consisted of a dose-finding portion based on a 3+3 design, followed by an expansion cohort. PF-03084014 was administered orally, twice daily (BID) for 21 continuous days. Tested doses ranged from 20 to 330 mg BID. In the expansion cohort, patients were to receive the estimated MTD or a lower dose of PF-03084014.A total of 64 patients received treatment. The MTD was estimated to be 220 mg BID. The RP2D was determined to be 150 mg BID, based on the better safety profile versus the 220-mg BID dose, given comparable NOTCH-related target inhibition. The most common treatment-related adverse events were diarrhea, nausea, fatigue, hypophosphatemia, vomiting, rash, and decreased appetite, which were generally mild to moderate in severity. One patient with advanced thyroid cancer had a complete response, and five of seven response-evaluable patients with desmoid tumor achieved a partial response (71.4% objective response rate). Tumor responses were mostly durable, ranging from 1.74+ to 24+ months. PF-03084014 demonstrated a generally dose-dependent pharmacokinetic profile at doses ranging from 20 to 330 mg BID. Consistent downmodulation of NOTCH-related HES4 gene expression was observed in peripheral blood from all evaluable patients.Further development of PF-03084014 for the treatment of patients with advanced solid tumors is warranted and currently under evaluation.
The Pharmacology of Carnitine
Authors: J J Bahl, R Bressler
Journal: The Annual Review of Pharmacology and Toxicology (1987)

Camitine (3-hydroxy-4-N-trimethylaminobutyric acid; see Figure 1) was iso­ lated from meat in 1905 ( l ). In 1959 Fritz (2) demonstrated that camitine has an obligatory role in long-chain fatty acid (LCFA) oxidation. Cederblad & Lindstedt (3) developed a sensitive assay in 1972, which was later modified by McGarry & Foster (4). This assay catalyzed investigation into the bio­ chemical role of L-camitine. These studies led to the administration of cami­ tine as a pharmacological agent in various situations. This use of camitine we view as derivative of its role in intermediary metabolism, generally related to fatty acid metabolism. We refer the reader to the primary literature, reviews, and books describing the physiological and biochemical role of camitine (5-9).
Enteric neurones modulate the colonic permeability response to luminal bile acids in rat colon in vivo
Authors: Y Sun
Journal: Gut (2004)

<b>Background:</b> The mechanisms behind microscopic colitis and exacerbations of ulcerative colitis are incompletely understood. It seems highly likely that both luminal antigens and bile are involved. The aim of this study was to test the hypothesis that bile acids increase colonic mucosal permeability by activating enteric neurones. <b>Method:</b> The effect of 4 mM deoxycholic acid (DCA) on the appearance rate of intravenously administered <sup>3</sup>H-mannitol and <sup>14</sup>C-urea into the lumen of the proximal and distal rat colon was measured in vivo and expressed as clearance. The nerve blocking agents atropine and hexamethonium were given intravenously, and lidocaine was applied onto the serosal surface of the colon, before and after DCA exposure <b>Results:</b> DCA markedly increased clearance of the permeability probes into the lumen in both colonic segments and also the ratio of mannitol/urea clearance, particularly in the distal colon. Pretreatment with atropine, hexamethonium, and lidocaine significantly inhibited the increase in clearance by approximately 65–80% but did not affect the clearance ratio. In the distal colon, the inhibitory effect of lidocaine was not statistically significant. Also, administration of atropine and hexamethonium after DCA exposure significantly inhibited the DCA effect on clearance of the probes. <b>Conclusion:</b> The results suggest that in vivo, the permeability increase induced by a moderate concentration of bile acid is to a large extent mediated by a neural mechanism involving muscarinic and nicotinic receptors. This mechanism may be a link between the central nervous system and colonic mucosal barrier function, and may be a new target for treatment.
Definition of Functionally Important Mechanistic Differences among Selective Estrogen Receptor Down-regulators
Authors: Bryan M. Wittmann, Andrea Sherk, Donald P. McDonnell
Journal: Cancer Research (2007)

Abstract One subclass of antiestrogens, the selective estrogen receptor down-regulators (SERDs), have received considerable attention of late as they competitively inhibit estrogen binding and induce a rapid, proteasome-dependent degradation of the receptor. Contained within this class of molecules is the steroidal antiestrogen ICI182,780 (faslodex), recently approved for the treatment of metastatic cancer, and GW5638/DPC974, a SERD that is currently being evaluated in the clinic. Given that mechanistic differences between different selective estrogen receptor modulators have been translated into important clinical profiles, it was of interest to determine if the SERD subclass of ligands were likewise functionally or mechanistically distinguishable. In this study, we show that although the steroidal and nonsteroidal SERDs target ERα for degradation, the underlying mechanism(s) are different. Of note was the identification of a specific protein-protein interaction surface presented on ERα in the presence of the ICI182,780-activated receptor which is required for degradation. Interestingly, this surface is also presented on ERα in the presence of RU58,668, a SERD that is chemically distinct from ICI182,780. This surface is not required for GW5638-mediated degradation, and thus, this SERD seems to affect ERα down-regulation by a different mechanism. These data suggest that sequencing of therapies using drugs of this class is likely to be possible. Finally, because of the unmet need for orally active SERDS that function similarly to ICI182,780, we have used the insights from these mechanistic studies to develop and validate a high-throughput screen for compounds of this class with improved pharmaceutical properties. [Cancer Res 2007;67(19):9549–60]
Catch Bonds in Adhesion
Authors: Wendy Thomas
Journal: Annual Review of Biomedical Engineering (2008)

One of the most exciting discoveries in biological adhesion is the recent and counter-intuitive observation that the lifetimes of some biological adhesive bonds, called catch bonds, are enhanced by tensile mechanical force. At least two types of adhesive proteins have been shown to form catch bonds--blood proteins called selectins and a bacterial protein called FimH. Both mediate shear-enhanced adhesion, in which cells bind more strongly at high shear than at low shear. Single-molecule experiments and cell-free assays have now clearly demonstrated that catch bonds exist and mediate shear-enhanced adhesion. However, the mechanics of cellular organelles also contribute to shear-enhanced adhesion by modulating the force applied to catch bonds. This review examines how individual catch bond behavior contributes to shear-enhanced cellular adhesion for the two best-understood examples. The lessons from these systems offer design principles for understanding other types of shear-enhanced adhesion and for engineering nanostructured force-dependent adhesives out of catch bonds.