tbuckley/cabot-search huggingface dataset:
Inhibition of Cholinergic Signaling Causes Apoptosis in Human Bronchioalveolar Carcinoma
Authors: Jamie K. Lau, Kathleen C. Brown, Brent A. Thornhill, Clayton M. Crabtree, Aaron M. Dom, Theodore R. Witte, W. Elaine Hardman, Christopher A. McNees, Cody A. Stover, A. Betts Carpenter, Haitao Luo, Yi C. Chen, Brandon S. Shiflett, Piyali Dasgupta
Journal: Cancer Research (2012)

Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BAC) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChR). In this study, we show that human BACs produce acetylcholine (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3), and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs, and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by α7-, α3β2-, and β3-nAChRs, ChAT and VAChT pathways. We observed that nicotine upregulated ChAT and VAChT. Therefore, we conjectured that VAChT antagonists, such as vesamicol, may suppress the growth of human BACs. Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or insulin-like growth factor-II-induced growth of human BACs. siRNA-mediated attenuation of VAChT reversed the apoptotic activity of vesamicol. We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy.
Treatment with licofelone prevents abnormal subchondral bone cell metabolism in experimental dog osteoarthritis
Authors: D Lajeunesse
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objectives:</b> To determine if treatment with licofelone, a combined 5-lipoxygenase and cyclo-oxygenase inhibitor, in vivo in experimental dog osteoarthritis can modify bone cell metabolism in long term in vitro subchondral osteoblast cell cultures (Ob). <b>Methods:</b> Group 1 received sectioning of the anterior cruciate ligament (ACL) of the right knee with no active treatment (placebo group). Groups 2 and 3 received sectioning of the ACL of the right knee, and were given licofelone (2.5 or 5.0 mg/kg daily by mouth, respectively) for eight weeks beginning the day after surgery. Primary Ob were prepared from the subchondral bone plate. Levels of phenotypic markers (alkaline phosphatase activity, osteocalcin release), and urokinase plasminogen activator (uPA) and insulin-like growth factor-1 (IGF-I) levels, were evaluated in each group. Lastly, prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) and leucotriene B<sub>4</sub> levels were evaluated. <b>Results:</b> No significant differences in alkaline phosphatase activity or osteocalcin release from Ob between the three groups, under either basal or 1,25(OH)<sub>2</sub>D<sub>3</sub> induction were seen. In contrast, treatment with licofelone reduced uPA and IGF-I levels in Ob. PGE<sub>2</sub> levels, which were still raised in the placebo group, were decreased sharply by licofelone. A relationship was found between licofelone treatment and either the reduction in the size of lesions on tibial plateaus or the levels of uPA, IGF-I, or PGE<sub>2</sub>. <b>Conclusions:</b> Licofelone treatment prevents and/or delays the abnormal metabolism of subchondral osteoblasts in this model. Licofelone reduced PGE<sub>2</sub> levels after long term Ob, suggesting that the reduction in uPA and IGF-I levels is linked, at least in part, to this reduction.
Endocardial endothelium modulates subendocardial pHi of rabbit papillary muscles: role of transendothelial HCO3? transport
Authors: P FRANSEN
Journal: Cardiovascular Research (2004)

This study investigated whether endocardial endothelial cells contribute to intracellular pH (pH(i)) regulation of subjacent cardiomyocytes.Right ventricular rabbit papillary muscles were loaded with the pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM) to measure pH(i) and HCO(3)(-) equivalent influx or efflux in muscles with intact endocardial endothelium (+EE) and in muscles with the endocardial endothelium removed (-EE).In steady-state conditions, pH(i) was consistently higher in +EE than in -EE muscles (7.38+/-0.03, n=39 vs. 7.27+/-0.04, n=20, p<0.05). In +EE muscles, removal of HCO(3)(-) from the buffer solution or adding 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of HCO(3)(-) transport, reduced pH(i) from 7.38 to 7.24+/-0.06 (n=14) and to 7.16+/-0.10 (n=10), respectively, whereas in -EE muscles pH(i) decreased slightly from 7.27 to 7.15+/-0.05 (n=14) and to 7.13+/-0.04 (n=7). In addition, HCO(3)(-) equivalent efflux during alkali loads by NH(4)Cl pulses was smaller in +EE muscles than in -EE muscles (0.89+/-0.50 vs. 1.99+/-0.12 mmol/l/min, n=5, p<0.05) and was inhibited by DIDS. HCO(3)(-) equivalent influx during recovery from acid load imposed upon wash out of NH(4)Cl, was larger in +EE muscles than in -EE muscles (2.15+/-0.54 mmol/l/min, n=6, vs. 1.06+/-0.20 mmol/l/min, n=5). 5-(N-Ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of Na(+)/H(+) exchange, decreased HCO(3)(-) equivalent influx by 50% in both muscle groups but influx was still significantly higher in +EE than in -EE muscles (1.18+/-0.23 vs. 0.57+/-0.07 mmol/l/min, p<0.05). Finally, endocardial endothelial cells cultured on collagen-coated inserts established a DIDS-sensitive transendothelial HCO(3)(-)gradient.These data suggest that the endocardial endothelium maintains transendothelial fluxes of HCO(3)(-) from luminal (blood) to basal (muscle) side of the cells, which modulate pH(i) regulation in subjacent cardiomyocytes.
Prognostic significance of S-phase kinase-associated protein 2 and p27kip1 in patients with diffuse large B-cell lymphoma: effects of rituximab
Authors: R Seki, K Ohshima, T Fujisaki, N Uike, F Kawano, H Gondo, S Makino, T Eto, Y Moriuchi, F Taguchi, T Kamimura, H Tsuda, K Shimoda, T Okamura
Journal: Annals of Oncology (2009)
<b><i>In Vitro</i></b>and<b><i>in Vivo</i></b>Cytotoxic Activities of Recombinant Immunotoxin 8H9(Fv)-PE38 against Breast Cancer, Osteosarcoma, and Neuroblastoma
Authors: Masanori Onda, Qing-cheng Wang, Hong-fen Guo, Nai-Kong V. Cheung, Ira Pastan
Journal: Cancer Research (2004)

Abstract The 8H9 monoclonal antibody (MAb) is highly reactive with a cell surface glycoprotein expressed on human breast cancers, childhood sarcomas, and neuroblastomas but is not reactive with the cell surface of normal human tissues. This specific reactivity suggests that MAb 8H9 may be useful for targeted cancer therapy. To explore this possibility, we generated two recombinant immunotoxins (ITs) using the single-chain Fv (scFv) of MAb 8H9. Initially the 8H9(scFv) cDNA was fused to a DNA encoding a 38-kDa truncated form of Pseudomonas exotoxin (PE38) to generate the IT 8H9(scFv)-PE38. The fusion gene was expressed in Escherichia coli, and the IT was purified to near homogeneity from inclusion bodies. The purified IT showed specific cytotoxicity on nine different cancer cell lines derived from breast cancer, osteosarcoma, and neuroblastomas, known to react with MAb 8H9. The cytotoxic activity was inhibited by MAb 8H9, showing the cytotoxic activity is specific. The antitumor activity of 8H9(scFv)-PE38 was evaluated in severe combined immunodeficient mice bearing MCF-7 breast cancers or OHS-M1 osteosarcomas. The IT showed a specific dose-dependent antitumor activity at 0.075 and 0.15 mg/kg. Next, a more stable disulfide-linked IT, 8H9(dsFv)-PE38, was constructed. It was produced in high yield (16%) and showed cytotoxic and antitumor activities similar to those of 8H9(scFv)-PE38. 8H9(dsFv)-PE38 was given to two cynomolgus monkeys at doses of 0.1 and 0.2 mg/kg i.v. QOD × 3 and was well tolerated. This shows that a dose that causes significant tumor regressions in mice is well tolerated by monkeys. These results make 8H9(dsFv)-PE38 a candidate for further development as a therapeutic agent for breast cancers, osteosarcomas, and neuroblastomas.
FRACTURES OF THE PATELLA
Authors: R. W. Jones
Journal: BMJ (1930)

r TN Bumut eft OCT.I I 9 119301 r~~~~~~~~~~~~~~~~~~~~~~~MEDICAL JOUNNAS come from the cells, since little or none had been given by the mouth, and that the water in the cells had been responsible for the high blood pressure.An opposite state of affairs would appear to have taken place between February 24th and 27th.The oedema subsided and the blood pressure rose.Apprehensive of further convulsions, the uterus was emptied on February 27th.The increase in the albuminuria during the same period is also significant.Allusions are to be found in the literature to the similarity, of the convulsions of eclampsia to those produced i,n animals by the continuous forced administration of water.Rowntr-ee and his co-workers20 discovered and investigated this latter phenomenon and termed it " water- irntoxication."It is characterized by a positive water balance, but this is correlated with an alteratioin in the sodium or base balance which results in a lowered amount of sodium in the plasma.Recovery from " water in- toxication " convulsions in animals is very rapid by tho use of intravenously or intraperitoneally administered hypertonic sodium chloride solution.The observations in this paper show a complete contrast in the action of hypertonic saline on eclampsia compared with " water intoxication " in animals.Moreover, Stander, Eastman, Harrison, anid Caddan2m have shown an increased amount of base in the plasma of eclamptics.This again is in contrast with the findings in " water intoxication " in animals.It would appear that, despite a similarity of the convulsive states in the two conditions, and that changes in the water balance are probably involved in both, a clear distinctionimust be made.McQuarrie,22 in his recent studies oni epilepsy, has drawn attention to its similarity with eclampsia, as well as " water intoxica- tion."According to the author the use of urea among other measures acts as a preventive against the seizures of epilepsy.Harding and Harris23 have recently in- vestigated the inifluence of urea solutions in "water intoxication " with negative results, and are thus inclined to dissociate it from epilepsy.Whether urea - will be of value in the treatmenit of eclampsia and pre-eclampsia, remains to be seen.
The response of patients with respiratory failure and cardiopulmonary disease to different levels of constant volume ventilation.
Authors: J Hedley-Whyte, H Pontoppidan, M J Morris
Journal: Journal of Clinical Investigation (1966)

The purpose of this study was to determine the effect of increasing the tidal volume on pulmonary ventilation-perfusion relations in patients with respiratory failure caused by cardiopulmonary disease.The frequent occurrence of an increased physio- logic dead space (2, 3) and of increased physio- logic shunting (3) in patients undergoing pro- longed artificial ventilation has previously been de- scribed.These changes in ventilation-perfusion ratios mean that very large tidal volumes and high percentages of inspired oxygen are often required to maintain life during prolonged intermittent posi- tive pressure ventilation.The aim of our study was to measure the consequences of changing the tidal volume, but not the respiratory frequency, of patients with respiratory failure secondary to either acute intrapulmonary infection or chronic pulmonary emphysema. MethodsSelection of patients.At the time of the study none of the twelve patients had a total vital capacity above 400 ml, and hence all were completely dependent on inter- mittent positive pressure ventilation.Eight of the pa- tients studied were selected because they had been free of symptomatic pulmonary disease on admission to the hospital, but had later developed nonemphysematous cardiopulmonary disease and acute intrapulmonary in- fection that caused respiratory failure.The diverse
A cloned human T cell line cytotoxic for autologous and allogeneic B lymphoma cells.
Authors: H Yssel, H Spits, J E de Vries
Journal: The Journal of Experimental Medicine (1984)

A human cytotoxic T cell clone (MWS-14) with auto-tumor reactivity was established in serum-free medium in a mixed tumor cell culture by repetitive stimulation with fresh autologous lymphoma cells. This clone and its subclones are of the T3+ T4+ T8- phenotype. They were strongly cytotoxic for the autologous lymphoma cells, whereas autologous PHA blasts were not killed. Analysis of the specificity of MWS-14, MWS-14-30, and MWS-14-34 indicated that these CTL clones were cytotoxic for 7/7 allogeneic lymphoma cells, whereas only 3/23 of normal and non-lymphoma cells were lysed. Blocking studies with monoclonal antibodies directed at MHC class I and class II antigens showed that this preferential, anti-lymphoma reactivity was not directed at HLA determinants. The anti-lymphoma activity is not due to an aspecific susceptibility of the lymphoma cells to lysis. In contrast to CTL clones specific for HLA antigens present on the lymphoma cells, T3 and T4 were not involved in the cytotoxic reaction of MWS-14 against the autologous lymphoma cells. The reactivity of this clone could be blocked by a monoclonal antibody directed at leukocyte function-associated antigen. It can be concluded from these results that these T4+ CTL clones recognize a determinant, which is preferentially expressed on autologous and allogeneic lymphoma cells.
Metabolic outcomes of three types of pulmonary rehabilitation: Endurance, resistance and combined training in patients with moderate to severe chronic obstructive pulmonary disease (COPD) in Costa Rica
Authors: Henry Delgado, Ronald Chacon
Journal: European Respiratory Journal (2013)

We compared three modalities of training in 20 patients with moderate to severe COPD (GOLD grade III and IV): endurance (aerobic), resistance (strength) and combined training (endurance +resistance) and compared them with a group of patients receiving regular COPD treatment without exercise intervention. The study was approved by the local ethics committee  We evaluated clinical parameters, lung function, arterial blood gases (ABG) and metabolic exercise tests in all of them before and after the rehabilitation program of 12 weeks. We found no significant difference in terms of heart rate, oxygen saturation, spirometry, ABG, before and after the program.  After the rehabilitation program there was a significant increase in the exercise time in all the rehabilitation groups compared with controls. There was a trend to increase in VOmax in all the groups but did not reach statistical significance. Anaerobic threshold was also significantly improved in the aerobic group. Our results support the importance of endurance and resistance training in COPD.
Imputation from 328 African Ancestry Genomes Reveals New Associations with Asthma in DPP10
Authors: Hironori Masuko, Nicholas M. Rafaels, Lili Huang, Sameer Chavan, James G. Wilson, L. Keoki Williams, Lorraine B. Ware, Carole Ober, Deborah A. Meyers, Tina V. Hartert, Marilyn Foreman, Jean G. Ford, Esteban Gonza Burchard, Eugene R. Bleecker, Georgia Dunston, Margaret Taub, Terri H. Beaty, Ingo Ruczinski, Rasika A. Mathias, Kathleen C. Barnes
Journal: Journal of Allergy and Clinical Immunology (2015)
Application of a New Multinomial Phase II Stopping Rule Using Response and Early Progression
Authors: S. Dent, B. Zee, J. Dancey, A. Hanauske, J. Wanders, E. Eisenhauer
Journal: Journal of Clinical Oncology (2001)

A multinomial stopping rule had previously been developed that incorporated both objective response and early progression into decisions to stop or continue phase II trials of anticancer agents. The purpose of this study was to apply the multinomial rule to two independent sets of phase II data to assess its utility in appropriately recommending early trial closure as compared with other stopping rules.Data from completed phase II trials of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and European Organization for Research and Treatment of Cancer Early Clinical Studies Group (ECSG) formed the basis of the study. Based on observed results for each trial, the recommendation of the multinomial stopping rule was applied, as was the recommendation of the actual stopping rule used (Fleming or Gehan). The appropriateness of the recommendations was evaluated based on interpretation of final study results.The standard and multinomial rules disagreed on early stopping in one of 16 NCIC CTG trials and in seven of 23 ECSG trials. In all cases, the standard rule advised continuing to the second stage whereas the multinomial rule advised stopping early because of excessive numbers of patients experiencing early disease progression. Final trial results indicated that the multinomial recommendation was appropriate, because in no study did final results lead to conclusions of activity.In this series of trials, the multinomial stopping rule performed more efficiently than the Fleming or Gehan rules in advising early stopping of trials. These results encourage continued exploration of this approach for phase II trials of cytotoxic and noncytotoxic anticancer agents.
Long-Term Mortality in Nationwide Cohorts of Childhood-Onset Type 1 Diabetes in Japan and Finland
Authors: Keiko Asao, Cinzia Sarti, Tom Forsen, Valma Hyttinen, Rimei Nishimura, Masato Matsushima, Antti Reunanen, Jaakko Tuomilehto, Naoko Tajima
Journal: Diabetes Care (2003)

OBJECTIVE—This study compares mortality from type 1 diabetes in Japan and Finland and examines the effects of sex, age at diagnosis, and calendar time period of diagnosis on mortality. RESEARCH DESIGN AND METHODS—Patients with type 1 diabetes from Japan (n = 1,408) and Finland (n = 5,126), diagnosed from 1965 through 1979, at age &amp;lt;18 years, were followed until 1994. Mortality was estimated with and without adjustment for that of the general population to assess absolute and relative mortality using Cox proportional hazard models. RESULTS—Overall mortality rates in Japan and Finland were 607 (95% CI 510–718) and 352 (315–393), respectively, per 100,000 person-years; standardized mortality ratios were 12.9 (10.8–15.3) and 3.7 (3.3–4.1), respectively. Absolute mortality was higher for men than for women in Finland, but relative mortality was higher for women than for men in both cohorts. Absolute mortality was higher in both cohorts among those whose diabetes was diagnosed during puberty, but relative mortality did not show any significant difference by age at diagnosis in either cohort. In Japan, both absolute and relative mortality were higher among those whose diagnosis was in the 1960s rather than the 1970s. CONCLUSIONS—Mortality from type 1 diabetes was higher in Japan compared with Finland. The increased risk of death from type 1 diabetes seems to vary by sex, age at diagnosis, and calendar time period of diagnosis. Further investigation, especially on cause-specific mortality, is warranted in the two countries.
The Human Trithorax Protein hASH2 Functions as an Oncoprotein
Authors: Juliane Lüscher-Firzlaff, Isabella Gawlista, Jörg Vervoorts, Karsten Kapelle, Till Braunschweig, Gesa Walsemann, Chantal Rodgarkia-Schamberger, Henning Schuchlautz, Stephan Dreschers, Elisabeth Kremmer, Richard Lilischkis, Christa Cerni, Axel Wellmann, Bernhard Lüscher
Journal: Cancer Research (2008)

Regulation of chromatin is an important aspect of controlling promoter activity and gene expression. Posttranslational modifications of core histones allow proteins associated with gene transcription to access chromatin. Closely associated with promoters of actively transcribed genes, trimethylation of histone H3 at lysine 4 (H3K4me3) is a core histone mark set by several protein complexes. Some of these protein complexes contain the trithorax protein ASH2 combined with the MLL oncoproteins. We identified human ASH2 in a complex with the oncoprotein MYC. This finding, together with the observation that hASH2 interacts with MLL, led us to test whether hASH2 itself is involved in transformation. We observed that hASH2 cooperates with Ha-RAS to transform primary rat embryo fibroblasts (REF). Furthermore, transformation of REFs by MYC and Ha-RAS required the presence of rAsh2. In an animal model, the hASH2/Ha-RAS-transformed REFs formed rapidly growing tumors characteristic of fibrosarcomas that, compared with tumors derived from MYC/Ha-RAS transformed cells, were poorly differentiated. This finding suggests that ASH2 functions as an oncoprotein. Although hASH2 expression at the mRNA level was generally not deregulated, hASH2 protein expression was increased in most human tumors and tumor cell lines. In addition, knockdown of hASH2 inhibited tumor cell proliferation. Taken together, these observations define hASH2 as a novel oncoprotein.
Phase I Study of Abagovomab in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Authors: Paul Sabbatini, Jakob Dupont, Carol Aghajanian, Felicia Derosa, Elizabeth Poynor, Sybil Anderson, Martee Hensley, Phillip Livingston, Alexia Iasonos, David Spriggs, William McGuire, Silke Reinartz, Sally Schneider, Cathy Grande, Shashikant Lele, Kerry Rodabaugh, James Kepner, Soldano Ferrone, Kunle Odunsi
Journal: Clinical Cancer Research (2006)

Abstract Purpose: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Experimental Design: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response. Results: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade &amp;gt;2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P = 0.6268), dose (P = 0.4602), or cohort (P = 0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL). Conclusions: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.