tbuckley/cabot-search huggingface dataset:
Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor–Positive Breast Cancer
Authors: José Baselga, Vladimir Semiglazov, Peter van Dam, Alexey Manikhas, Meritxell Bellet, José Mayordomo, Mario Campone, Ernst Kubista, Richard Greil, Giulia Bianchi, Jutta Steinseifer, Betty Molloy, Erika Tokaji, Humphrey Gardner, Penny Phillips, Michael Stumm, Heidi A. Lane, J. Michael Dixon, Walter Jonat, Hope S. Rugo
Journal: Journal of Clinical Oncology (2009)

Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001).Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry.Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone (ie, placebo; 68.1% v 59.1%), which was statistically significant at the preplanned, one-sided, alpha = 0.1 level (P = .062). Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms, and dramatic downregulation of phospho-S6 occurred only in the everolimus arm. An antiproliferative response, as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15, occurred in 52 (57%) of 91 patients in the everolimus arm and in 25 (30%) of 82 patients in the placebo arm (P < .01). The safety profile was consistent with historical results of everolimus monotherapy; grades 3 to 4 adverse events occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo.Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.
Symptoms of asthma, bronchial responsiveness and atopy in immigrants and emigrants in Europe
Authors: A.F. Kalyoncu
Journal: European Respiratory Journal (2002)

To the Editor: 

I read with interest the article by Tobias et al. 1. Firstly, I would like to state my doubts on the validity and relevance of using the umbrella term “immigrants” in reference to people from various countries of the world who settle in developed countries.

Most of the time, leaving one's home country is not a deliberate action. The main initiatives are related to economical and political reasons. Those who immigrate for economical reasons usually use legal routes. The legal process makes it obligatory to have a health check and does not permit diseased individuals to migrate. This obligation does not hold true for the immigrants who leave their countries for political reasons. Political immigrants are however, still expected to have a relatively better health status than the general population to enable them to escape the legal barriers and leave their country. The observation in Turkish …
Effects of bile acids on pancreatic ductal bicarbonate secretion in guinea pig
Authors: V Venglovecz, Z Rakonczay, B Ozsvari, T Takacs, J Lonovics, A Varro, M A Gray, B E Argent, P Hegyi
Journal: Gut (2008)

<h3>Background and aims:</h3> Acute pancreatitis is associated with significant morbidity and mortality. Bile reflux into the pancreas is a common cause of acute pancreatitis and, although the bile can reach both acinar and ductal cells, most research to date has focused on the acinar cells. The aim of the present study was to investigate the effects of bile acids on HCO<sub>3</sub><sup>−</sup> secretion from the ductal epithelium. <h3>Methods:</h3> Isolated guinea pig intralobular/interlobular pancreatic ducts were microperfused and the effects of unconjugated chenodeoxycholate (CDC) and conjugated glycochenodeoxycholate (GCDC) on intracellular calcium concentration ([Ca<sup>2+</sup>]<sub>i</sub>) and pH (pH<sub>i</sub>) were measured using fluorescent dyes. Changes of pH<sub>i</sub> were used to calculate the rates of acid/base transport across the duct cell membranes. <h3>Results:</h3> Luminal administration of a low dose of CDC (0.1 mM) stimulated ductal HCO<sub>3</sub><sup>−</sup> secretion, which was blocked by luminal H<sub>2</sub>DIDS (dihydro-4,4′-diisothiocyanostilbene-2,2′-disulfonic acid). In contrast, both luminal and basolateral administration of a high dose of CDC (1 mM) strongly inhibited HCO<sub>3</sub><sup>−</sup> secretion. Both CDC and GCDC elevated [Ca<sup>2+</sup>]<sub>i</sub>, and this effect was blocked by BAPTA-AM (1,2-bis(<i>o</i>-aminophenoxy)ethane-<i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>′-tetra-acetic acid), caffeine, xestospongin C and the phospholipase C inhibitor U73122. BAPTA-AM also inhibited the stimulatory effect of low doses of CDC on HCO<sub>3</sub><sup>−</sup> secretion, but did not modulate the inhibitory effect of high doses of CDC. <h3>Conclusions:</h3> It is concluded that the HCO<sub>3</sub><sup>−</sup> secretion stimulated by low concentrations of bile acids acts to protect the pancreas against toxic bile, whereas inhibition of HCO<sub>3</sub><sup>−</sup> secretion by high concentrations of bile acids may contribute to the progression of acute pancreatitis.
Theophylline and selective phosphodiesterase inhibitors as anti-inflammatory drugs in the treatment of bronchial asthma
Authors: KH Banner, CP Page
Journal: European Respiratory Journal (1995)

Theophylline has been in clinical use for the treatment of bronchial asthma and other respiratory diseases for well over 50 yrs. Over this time, a considerable body of evidence has accumulated to show that this drug has a wide range of pharmacological actions, in addition to the well-recognized action on airway smooth muscle function. Current evidence suggests that part of the therapeutic value of theophylline in the treatment of asthma is by virtue of an anti-inflammatory or immunomodulatory effect, although the actual mechanism of action remains unclear. It has been proposed that the observed anti-inflammatory effects of theophylline could be attributed to phosphodiesterase (PDE) inhibition, and recently the type III and IV isoenzymes have been characterized in a number of inflammatory cells. This article reviews the evidence that theophylline and the newer more selective type IV PDE isoenzyme inhibitors can inhibit the activation of inflammatory cell types, such as T-lymphocytes, eosinophils, mast cells and macrophages, in vitro. The evidence supporting the ability of theophylline and selective PDE IV isoenzyme inhibitors to modify allergic inflammation both in animal models and clinical asthma is also discussed. We conclude that theophylline possesses important anti-inflammatory and immunomodulatory activity and that, in light of this evidence, it is timely to reconsider the place of theophylline in the treatment of asthma.
Impact of Serum Hepatocyte Growth Factor on Treatment Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non–Small Cell Lung Adenocarcinoma
Authors: Kazuo Kasahara, Tokuzo Arao, Kazuko Sakai, Kazuko Matsumoto, Asao Sakai, Hideharu Kimura, Takashi Sone, Atsushi Horiike, Makoto Nishio, Tatsuo Ohira, Norihiko Ikeda, Takeharu Yamanaka, Nagahiro Saijo, Kazuto Nishio
Journal: Clinical Cancer Research (2010)

The epidermal growth factor receptor (EGFR) mutation status has emerged as a validated biomarker for predicting the response to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small cell lung cancer. However, the responses to EGFR-TKIs vary even among patients with EGFR mutations. We studied several other independently active biomarkers for EGFR-TKI treatment.We retrospectively analyzed the serum concentrations of 13 molecules in a cohort of 95 patients with non-small cell lung adenocarcinoma who received EGFR-TKI treatment at three centers. The pretreatment serum concentrations of amphiregulin, β-cellulin, EGF, EGFR, epiregulin, fibroblast growth factor-basic, heparin-binding EGF-like growth factor, hepatocyte growth factor (HGF), platelet-derived growth factor β polypeptide, placental growth factor, tenascin C, transforming growth factor-α, and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay and a multiplex immunoassay system. The associations between clinical outcomes and these molecules were evaluated.The concentrations of HGF and VEGF were significantly higher among patients with progressive disease than among those without progressive disease (P < 0.0001). HGF and VEGF were strongly associated with progression-free survival (PFS) and overall survival (OS) in a univariate Cox analysis (all tests for hazard ratio showed P < 0.0001). A stratified multivariate Cox model according to EGFR mutation status (mutant, n = 20; wild-type, n = 23; unknown, n = 52) showed that higher HGF levels were significantly associated with a shorter PFS and OS (P < 0.0001 for both PFS and OS). These observations were also consistent in the subset analyses.Serum HGF was strongly related to the outcome of EGFR-TKI treatment. Our results suggest that the serum HGF level could be used to refine the selection of patients expected to respond to EGFR-TKI treatment, warranting further prospective study.
Computer Tomographic Assessment of Perfluorocarbon and Gas Distribution during Partial Liquid Ventilation for Acute Respiratory Failure
Authors: MICHAEL QUINTEL, RONALD B. HIRSCHL, HARRY ROTH, REINHARD LOOSE, KLAUS van ACKERN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The average in vivo chest computed tomographic (CT) attenuation number (air = − 1,000, soft tissue = 0, perflubron = + 2,300 Hounsfield units [HU]) of 10 ventrodorsal-oriented lung segments was calculated to assess the distribution of gas and perflubron in 14 oleic acid lung-injured adult sheep during partial liquid ventilation (PLV, n = 7) or gas ventilation (GV, n = 7). Partial liquid ventilation was associated with a significant decrease in shunt fraction (PLV = 40 ± 12%, GV = 76 ± 12%, p = 0.004). Computed tomographic attenuation data during expiration (HUexp) demonstrated minimal gas aeration in GV animals in the dependent (segments 6–10) lung zones (HUexp = − 562 ± 108 for segments 1–5, HUexp = − 165 ± 104 for segments 6–10, p = 0.015). During PLV, perflubron was predominantly distributed to the dependent lung regions (HUexp = 579 ± 338 for segments 1–5, HUexp = 790 ± 149 for segments 6–10, p = 0.04). The ratio of the inspiratory to expiratory HU (HUinsp/exp) was greater in dependent than nondependent regions (mean HUinsp/exp segments 1–5 = 0.56, segments 6–10 = 0.81, p = 0.01), indicating that during inspiration relatively more gas than perflubron was distributed to the nondependent lung regions. We conclude that during PLV in this lung injury model, (1) gas exchange is improved when compared with gas ventilation, (2) perflubron is distributed predominantly to the dependent regions of the lung, and (3) although gas is distributed throughout the lung with each inspiration, more gas than perflubron goes to the nondependent lung regions.
What have we learned about intrahepatic cholestasis of pregnancy?
Authors: Humberto Reyes
Journal: Hepatology (2015)

1Department of Medicine, Faculty of MedicineUniversity of ChileSantiago de Chile *Address reprint requests to: Humberto Reyes, M.D., Professor Emeritus, Departamento de Medicina Oriente, Facultad de Medicina, Universidad de Chile, Av. Salvador 486-Providencia, Santiago de Chile. E‐mail: [email protected].
Alcohol strategy is short on targets and ambitions, MPs told
Authors: A. O'Dowd
Journal: BMJ (2012)

The government’s alcohol strategy to tackle binge drinking and introduce a minimum unit price for alcohol lacks targets and is not ambitious enough, say alcohol experts.

Witnesses at the first oral evidence session of the parliamentary health select committee’s new inquiry into the government’s alcohol plans said the government’s strategy launched last month was welcome in many ways but did not go far enough.

At the evidence session on 17 April, alcohol experts said there was too little emphasis in the strategy on the health impacts of alcohol and how treatment for people with a drinking problem can be improved.

Under the alcohol strategy, published last month by the Home Office, there are plans to introduce a minimum unit …
Regional cerebral blood flow during mechanical hyperventilation in patients with fulminant hepatic failure
Authors: Gitte Irene Strauss, Peter Høgh, Kirsten Møller, Gitte Moos Knudsen, Bent Adel Hansen, Fin Stolze Larsen
Journal: Hepatology (1999)

Hyperventilation is frequently used to prevent or postpone the development of cerebral edema and intracranial hypertension in patients with fulminant hepatic failure (FHF). The influence of such therapy on regional cerebral blood flow (rCBF) remains, however, unknown. In this study the CBF-distribution pattern was determined within the first 12 hours after development of hepatic encephalopathy (HE) stage 4 before and during hyperventilation. Ten consecutive patients (median age 48 [range 33-57] years) with FHF and 9 healthy controls (median age 54 [24-58] years) had rCBF determined by single photon emission computed tomography (SPECT) using intravenous injection of 133Xenon. For determination of high resolution CBF pattern, the patients were also studied with 99mTc-hexa-methylpropyleneamine oxime (HMPAO) in the hyperventilation condition. There was no significant difference in the rCBF distribution pattern during normoventilation as compared with hyperventilation. The anterior to posterior (AP) ratio was significantly lower in patients as compared with healthy controls. After hepatic recovery and disappearance of HE, 3 patients had restored normal rCBF distribution pattern as compared with healthy controls. We conclude that in sedated patients with FHF, a relatively lower rCBF is found in the frontal regions and in the basal ganglia as compared with posterior regions. This rCBF-distribution pattern was not aggravated during hyperventilation. It is speculated that this change of rCBF in patients with FHF may render the frontal brain regions more susceptible to hypoxia. The relative frontal rCBF decrease was shown to be reversible with hepatic recovery and alleviation of HE.
Targeting the Deregulated Spliceosome Core Machinery in Cancer Cells Triggers mTOR Blockade and Autophagy
Authors: Virginie Quidville, Samar Alsafadi, Aïcha Goubar, Frédéric Commo, Véronique Scott, Catherine Pioche-Durieu, Isabelle Girault, Sonia Baconnais, Eric Le Cam, Vladimir Lazar, Suzette Delaloge, Mahasti Saghatchian, Patricia Pautier, Philippe Morice, Philippe Dessen, Stéphan Vagner, Fabrice André
Journal: Cancer Research (2013)

The spliceosome is a large ribonucleoprotein complex that guides pre-mRNA splicing in eukaryotic cells. Here, we determine whether the spliceosome could constitute an attractive therapeutic target in cancer. Analysis of gene expression arrays from lung, breast, and ovarian cancers datasets revealed that several genes encoding components of the core spliceosome composed of a heteroheptameric Sm complex were overexpressed in malignant disease as compared with benign lesions and could also define a subset of highly aggressive breast cancers. siRNA-mediated depletion of SmE (SNRPE) or SmD1 (SNRPD1) led to a marked reduction of cell viability in breast, lung, and melanoma cancer cell lines, whereas it had little effect on the survival of the nonmalignant MCF-10A breast epithelial cells. SNRPE or SNRPD1 depletion did not lead to apoptotic cell death but autophagy, another form of cell death. Indeed, induction of autophagy was revealed by cytoplasmic accumulation of autophagic vacuoles and by an increase in both LC3 (MAP1LC3A) protein conversion and the amount of acidic autophagic vacuoles. Knockdown of SNRPE dramatically decreased mTOR mRNA and protein levels and was accompanied by a deregulation of the mTOR pathway, which, in part, explains the SNRPE-dependent induction of autophagy. These findings provide a rational to develop new therapeutic agents targeting spliceosome core components in oncology.
The in vitro effects of Bordetella pertussis lymphocytosis-promoting factor on murine lymphocytes. III. B-cell dependence for T-cell proliferation.
Authors: M K Ho, A S Kong, S I Morse
Journal: The Journal of Experimental Medicine (1979)

The nature of the helper lymphocytes in lymphocytosis-promoting factor (LPF)-induced proliferation was explored. Removal of macrophages from adherent splenocytes by either carbonyl-iron incubation or passage through Sephadex G-10 columns did not affect their synergistic function. Nor did cytolysis with Thy-1.2 antiserum and complement. The helper cells were found to be surface immunoglobulin-positive (sIg+) because they are retained by anti-Ig columns, susceptible to lysis by rabbit anti-mouse immunoglobulin and complement, and occurred in the sIg+ fractions of splenocytes after separation on the fluorescence-activated cell sorter. Further delineation of the surface markers on helper cells showed that complement receptors are not the determining marker for synergistic function. The requirement for B-helper cells in the stimulation of T lymphocytes by LPF is unique for a mouse of T-cell mitogen.
Expectations of assisted conception for infertility.
Authors: M. G. Hull, H. A. Eddowes, U. Fahy, M. I. Abuzeid, M. S. Mills, D. J. Cahill, C. F. Fleming, P. G. Wardle, W. C. Ford, A. McDermott
Journal: BMJ (1992)

OBJECTIVE--To provide reliable prognostic information for couples seeking assisted conception. DESIGN--Analysis of four years9 practice (1988-91). SETTING--Private university service linked with NHS reproductive medicine services. PATIENTS--804 couples with various causes of subfertility, median duration five years, median age of women 34 years. INTERVENTIONS--1280 completed cycles: 950 in vitro fertilisation, 144 gamete intrafallopian transfer, and 186 intrauterine insemination and superovulation. MAIN OUTCOME MEASURES--Pregnancy and birth rates per cycle and cumulative pregnancy and take home baby rates per couple. RESULTS--In women under 40 years and men with normal sperm, whatever the cause of infertility, results with in vitro fertilisation improved steadily reaching a pregnancy rate per cycle of 30% (95% confidence interval 26% to 35%) during 1990-1 and birth rate per cycle of 29% (23% to 35%) in 1990. Pregnancy and birth rates for gamete intrafallopian transfer were 36% (28% to 44%) and 26% (17% to 37%) and for intrauterine insemination 18% (12% to 24%) and 16% (10% to 22%). After six cycles cumulative probability of pregnancy was 82% and cumulative take home baby rate 70%. Considering only in vitro fertilisation and gamete intrafallopian transfer after four cycles the pregnancy rate was 78% (66% to 91%). CONCLUSIONS--Conception is less likely in women over 40 and men with sperm dysfunction. For other couples the prognosis for a live birth is at least as good as for fertile couples if they persist with treatment.
Preventing a paradigm shift: A plea for the computational genome
Authors: Carmine Garzillo, Giuseppe Trautteur
Journal: Behavioral and Brain Sciences (2012)

Abstract Against the opinion that DNA as program is not sufficiently explanatory, we maintain that the cellular machinery is entirely computational, and we identify the crucial notion of the interpreter that expresses the gene with the minimal gene set. Epigenetics research does not so much need paradigm shifts as the unraveling of an exceedingly complex computational machine.
Neisserial porins induce B lymphocytes to express costimulatory B7-2 molecules and to proliferate.
Authors: L M Wetzler, Y Ho, H Reiser, L W Wetzler
Journal: The Journal of Experimental Medicine (1996)

The neisserial porins are the major protein components of the outer membrane of the pathogenic Neisseria (N. meningitidis and N. gonorrhoeae). They have been shown to be able to enhance the immune response to poorly immunogenic substances (e.g., polysaccharides, peptides, glycolipids, etc.). To explore the basis of their potent adjuvant activity, the effect of the neisserial porins on T-B cell interactions and T cell costimulation was examined. Neisserial porins increased the surface expression of the costimulatory ligand B7-2 (CD86) but did not affect the expression of B7-1 (CD80). In addition, incubation with the neisserial porins increased the T lymphocyte costimulatory ability of B lymphocytes, which was inhibited by anti-B7-2 but not anti-B7-1 monoclonal antibodies. Upregulation of B7-2 on the surface of B lymphocytes may be the mechanism behind the immunopotentiating activity of neisserial porins.
Phospholamban Knockout Breaks Arrhythmogenic Ca <sup>2+</sup> Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice
Authors: Yunlong Bai, Peter P. Jones, Jiqing Guo, Xiaowei Zhong, Robert B. Clark, Qiang Zhou, Ruiwu Wang, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, Lisa Semeniuk, Ang Guo, Long-Sheng Song, Henry J. Duff, S.R. Wayne Chen
Journal: Circulation Research (2013)

Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca²⁺ ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca²⁺ load and Ca²⁺ leak. Conversely, PLN-KO accelerates Ca²⁺ sequestration and aborts arrhythmogenic spontaneous Ca²⁺ waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca²⁺-triggered arrhythmias.We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT.We generated a PLN-deficient, RyR2-mutant mouse model (PLN-/-/RyR2-R4496C+/-) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT-associated RyR2-R4496C mutant mice. Ca²⁺ imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C+/- ventricular myocytes during sarcoplasmic reticulum Ca²⁺ overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca²⁺ sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca²⁺ overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca²⁺ ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li⁺ failed to convert mini-waves to cell-wide SCWs in PLN-/-/RyR2-R4496C+/- ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs.Our results demonstrate that despite severe sarcoplasmic reticulum Ca²⁺ leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca²⁺ sequestration represents an effective approach for suppressing Ca²⁺-triggered arrhythmias.
Evidence of recursion in tool use
Authors: Lluís Barceló-Coblijn, Antoni Gomila
Journal: Behavioral and Brain Sciences (2012)

Abstract We discuss the discovery of technologies involving knotted netting, such as textiles, basketry, and cordage, in the Upper Paleolithic. This evidence, in our view, suggests a new way of connecting toolmaking and syntactic structure in human evolution, because these technologies already exhibit an “infinite use of finite means,” which we take to constitute the key transition to human cognition.