tbuckley/cabot-search huggingface dataset:
Hemiasterlin analogs exclusively label α-tubulin at the interdimer region and specifically block subtilisin digestion of α-tubulin
Authors: Malathi Hari, Maria Nunes, Arie Zask, Joshua Kaplan, Joseph Wooters, Albert A. Minnick, Michael K. May, Sylvia Musto, Carl Beyer, Girija Krishnamurthy, Yongchang Qiu, Frank Loganzo, Semiramis Ayral-Kaloustian, Lee M. Greenberger
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

5441 

HTI-286, a synthetic analog of hemiasterlin, is a novel tripeptide that depolymerizes microtubules. The binding-sites on tubulin of antimitotic peptides such as hemiasterlin and dolastatin-10 are not well characterized. To determine the binding site for HTI-286 two radiolabeled benzophenone photoaffinity probes of HTI-286 were utilized. We have already established that photoprobe 1 binds within residues 314-338 of α-tubulin. Here we describe the binding of photoprobe 2 (N,β,β-trimethyl-L-phenylalanyl-4-benzoyl-N-[(1S,2E)-3-carboxy-1-isopropyl-2-butenyl]-N,β,β-trimethyl-L-phenylalaninamide). The affinity of probe 2 for bovine brain tubulin was determined to be 3.6 μM, 6-fold higher than that for HTI-286. HTI-286 and probe 2 inhibited tubulin polymerization in a cell-free system by 88% and 69%, respectively. Probe 2 was 20-fold less potent in its ability to inhibit cell growth (IC50 = 22nM). Radiolabeled probe 2 exclusively labeled the α-subunit in bovine brain and HeLa cell tubulin preparations. Photolabeling of tubulin was inhibited by unlabeled photoaffinity analog, HTI-286, vinblastine, and dolastatin-10. However, some concentrations of paclitaxel and colchicine enhanced binding of probe 2. Digestion of labeled tubulin with trypsin, formic acid, Lys C, and CNBr suggests that probe 2 binds N-terminal to residue 306 (formic acid cleavage site), and is likely to reside within amino acids 204-280 in α-tubulin. These and other data from our laboratory suggest that the HTI-286 binding site maps to α-tubulin at the interdimer region. This region has not been reported as a binding site for any other known tubulin-binding drug. The C-terminal (2-4 kDa) regions of α- and β-tubulin are susceptible to cleavage by subtilisin under non-denaturing conditions. Subtilisin cleaves β-tubulin more rapidly than α-tubulin. Vinblastine and dolastatin-10 binding induces polymerization of tubulin into non-microtubule structures that pellet at 100,000 g . Vinblastine-induced polymerization can block limited proteolysis (at room temperature) with subtilisin of α-tubulin, but not β-tubulin. We observed that HTI-286 does not cause tubulin to polymerize into structures that pellet at 100,000 g , but nevertheless protects the subtilisin cleavage site in α-tubulin. This suggests that the mechanism of protection of α-tubulin by HTI-286 is distinct from that seen by vinblastine and dolastatin-10. We propose that the protection of subtilisin-cleavage is due to a change in the conformation of the C-terminus upon binding of HTI-286 to α-tubulin. Taken together these data strongly suggest that HTI-286 binds to α-tubulin in the interdimer region.
First Study of Infliximab Treatment in Patients with Chronic Obstructive Pulmonary Disease
Authors: Hester van der Vaart, Gerard H. Koëter, Dirkje S. Postma, Henk F. Kauffman, Nick H. T. ten Hacken
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Tumor necrosis factor-alpha is believed to be important in the induction and maintenance of airway inflammation in chronic obstructive pulmonary disease.We aimed to evaluate the effect of the anti-tumor necrosis factor-alpha drug infliximab in patients with chronic obstructive pulmonary disease, with percentage of sputum neutrophils as the primary endpoint.We performed an exploratory single-center, double-blind, placebo-controlled, randomized, phase 2 trial in which 22 current smokers with mild-to-moderate chronic obstructive pulmonary disease participated. Fourteen patients received three infusions of infliximab (5 mg/kg) at Weeks 0, 2, and 6, and eight patients received placebo infusions. Sputum samples, respiratory symptoms, quality of life, exhaled nitric oxide, lung function parameters, bronchial hyperresponsiveness, resting energy expenditure, and side effects were evaluated.This study did not show a positive short-term effect of infliximab on airway inflammation, lung function, resting energy expenditure, or quality of life. Exhaled nitric oxide increased significantly at Day 2, Week 6, and Week 8 in patients receiving infliximab compared with those receiving placebo. Eight patients in the infliximab group (vs. none in the placebo group) reported increased coughing, but no serious adverse events or increase in respiratory infections were reported during 9 weeks of follow-up.In this short-term study, no clinically beneficial effects of infliximab were observed, and there were no significant safety issues. Definite conclusions concerning the effectiveness of infliximab treatment in chronic obstructive pulmonary disease await additional studies, including those with a larger number of patients with more advanced disease.
Role of Lymphocyte Adhesion Receptors in Transient Interactions and Cell Locomotion
Authors: M L Dustin, T A Springer
Journal: Annual Review of Immunology (1991)

Lymphocytes adhere to other cells and extracellular matrix in the process of immunological recognition and lymphocyte recirculation. This review focuses on regulation of lymphocyte adhesion and the use of adhesion mechanisms by lymphocytes to obtain information about their immediate environment. The CD2 and LFA-1 adhesion receptors appear to have distinct roles in the regulation of adhesion and modulation of T lymphocyte activation. Adhesion mediated by interaction of CD2 with LFA-3 is dramatically altered by surface charge and adhesion receptor density in such a way that this pathway is latent in resting T lymphocytes but becomes active over a period of hours following T-cell activation. CD2 ligation can mediate or enhance T-cell activation, suggesting that signals from CD2/LFA-3 adhesive interactions are integrated with signals from the T-cell antigen receptor during immunological recognition. A model for the role of LFA-3 lateral diffusion in adhesion is presented, based on the lateral diffusion of different LFA-3 forms in glass supported planar membranes. Interaction of LFA-1 with ICAMs is also regulated by cell activation but in a different way than in interaction of CD2 with LFA-3. LFA-1 avidity for ICAMs is transiently increased by T-cell activation over a period of minutes. Cycles of avidity change are also observed for other T lymphocyte integrins which bind to extracellular matrix components. We propose that integrin avidity cycles may have an important role in the interconnected phenomena of locomotion, initial cell-cell adhesion, and cell-cell deadhesion. Recent observations on recirculation of T lymphocyte subpopulations are discussed in the context of general lessons learned from study of the CD2/LFA-3 and LFA-1/ICAM adhesion mechanisms.
Platinum analogue combination chemotherapy: cisplatin and carboplatin--a phase I trial with pharmacokinetic assessment of the effect of cisplatin administration on carboplatin excretion.
Authors: D L Trump, J L Grem, K D Tutsch, J K Willson, K J Simon, D Alberti, B Storer, D C Tormey
Journal: Journal of Clinical Oncology (1987)

Cisplatin (NSC 119875) and carboplatin (NSC 241240) are platinum (II) analogues with very different spectra of toxicity. Cisplatin dose is limited by nausea and vomiting, renal dysfunction, and dose-related peripheral neuropathy, whereas carboplatin is myelosuppressive. There are also clinical and laboratory data that suggest that these drugs may not be completely cross-resistant. Therefore, the following phase I trial of combination therapy with cisplatin and carboplatin was undertaken. Since carboplatin toxicity is enhanced in the presence of renal impairment, carboplatin excretion was also evaluated in selected patients at the maximum tolerated dose. Thirty-three patients received 50 mg/m2 cisplatin and doses of carboplatin between 160 mg/m2 and 400 mg/m2. Sequential 20-minute infusions of carboplatin and then cisplatin were able to be administered at the standard doses of carboplatin (320 and 400 mg/m2) with thrombocytopenia to the degree expected if carboplatin alone had been given. However, 280 mg/m2 carboplatin followed by 25 mg/m2 cisplatin/d X 3 caused unexpectedly severe thrombocytopenia in seven of eight patients (median platelet nadir 45,000/microL; range, 12 to 321,000/microL; nadir was less than 90,000 in seven of eight patients). In three patients treated with 280 mg/m2 carboplatin plus 25 mg/m2/d X 3 cisplatin, pharmacokinetics of carboplatin were compared during consecutive monthly cycles without and with cisplatin. Modestly increased areas under the curve (AUC) for carboplatin (15% and 35%) with cisplatin were seen in the two patients who experienced more pronounced platelet suppression with combination therapy. No other limiting or unusual toxicity was seen with this combination. Responses, primarily in "platinum responsive" tumors, were seen. The combination of cisplatin plus carboplatin is feasible and merits further study.
A comprehensive urinary proteome analysis: potential applications in disease biomarker discovery and validation
Authors: Mindi Zhao, Menglin Li, Yehong Yang, Dandan Gao, Zhengguang Guo, Yang Zhang, Yongji Tian, Nan Ji, Ying Sun, Chen Shao, Liwei Zhang, Mingxi Li, Wei Sun, Youhe Gao
Journal: The Lancet (2015)
Asbestos: Mechanisms of Toxicity and Carcinogenicity in the Respiratory Tract
Authors: B Mossman, W Light, E Wei
Journal: The Annual Review of Pharmacology and Toxicology (1983)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma
Authors: Ritesh Agarwal, Ashutosh N. Aggarwal, Sahajal Dhooria, Inderpaul Singh Sehgal, Mandeep Garg, Biman Saikia, Digambar Behera, Arunaloke Chakrabarti
Journal: European Respiratory Journal (2015)

Whether use of high-dose steroids in acute-stage allergic bronchopulmonary aspergillosis (ABPA) is associated with superior outcomes is not known. Herein, we compare the efficacy and safety of two glucocorticoid protocols in ABPA. Treatment-naive ABPA subjects randomly received either high-dose or medium-dose oral prednisolone. The primary outcomes were exacerbation rates and glucocorticoid-dependent ABPA after 1 and 2 years, respectively, of treatment. The secondary end-points were composite response rates after 6 weeks, improvement in lung function, time to first exacerbation, cumulative dose and adverse effects. 92 subjects (high-dose n=44, medium-dose n=48) were included in the study. The numbers of subjects with exacerbation after 1 year (high-dose 40.9% versus medium-dose 50%, p=0.59) and glucocorticoid-dependent ABPA after 2 years (high-dose 11.4% versus medium-dose 14.6%, p=0.88) were similar in the two groups. Although composite response rates were significantly higher in the high-dose group, improvement in lung function and time to first exacerbation were similar in the two groups. Cumulative glucocorticoid dose and side-effects were significantly higher in the high-dose group. Medium-dose oral glucocorticoids are as effective and safer than high-dose in treatment of ABPA.
Ventral Striatal Activation During Reward Processing in Psychosis
Authors: Joaquim Radua, André Schmidt, Stefan Borgwardt, Andreas Heinz, Florian Schlagenhauf, Philip McGuire, Paolo Fusar-Poli
Journal: JAMA Psychiatry (2015)

IMPORTANCE Abnormal reward processing is suggested to underlie the formation of psychotic symptoms, likely driven by elevated ventral striatal (VS) dopamine levels.Functional magnetic resonance imaging studies reveal alterations of VS activity during reward processing in patients with chronic psychosis and first episode of psychosis, as well as individuals at high risk for psychosis, but findings are inconclusive, conflicting, and difficult to subject to meta-analysis without introducing bias because several studies reported that findings were not statistically significant but did not report statistics.OBJECTIVE To assess the differences between patients with schizophrenia spectrum disorders and healthy controls in VS activation during reward processing.DATA SOURCES Web of Knowledge database (incorporating Web of Science and MEDLINE) until July 2015, including references of eligible articles and reviews.STUDY SELECTION Functional magnetic resonance imaging studies comparing VS activity during monetary reward processing between patients with schizophrenia spectrum disorders or clinical or genetic high-risk state for psychosis and healthy controls.DATA EXTRACTION AND SYNTHESIS Statistics and thresholds related to the main outcome measures and potential moderators were independently retrieved by 2 investigators.Effect sizes were analyzed using MetaNSUE, a random-effects method that enables the unbiased inclusion of nonstatistically significant unreported effects. MAIN OUTCOMES AND MEASURESEffect size of the group differences in VS activity, and correlation between VS activity and negative and positive symptom scores in patients. RESULTSThe meta-analysis included 23 studies (917 patients) for reward anticipation, 9 studies (358 patients) for reward feedback, and 8 studies (314 patients) for reward prediction error.We found significant bilateral VS hypoactivation during reward anticipation (23 studies, n = 917) in patients compared with healthy controls (left/right Cohen d, -0.50/-0.70;P< .001).Left VS abnormality was more severe in patients with high scores of negative symptoms during reward anticipation (r=-0.41;P< .001).Patients also showed hypoactivation during reward feedback (left/right d, -0.57/-0.56;P< .001).Simulations showed that exclusion of studies with nonstatistically significant unreported effects was associated with a strong bias (d bias=0.22),whereas estimations using MetaNSUE were unbiased even when statistics were seldom reported (d bias < 0.001). CONCLUSIONS AND RELEVANCEThis meta-analysis provides evidence that patients with psychosis demonstrate VS hypoactivation during reward anticipation.The assessment of VS prediction errors seems to be promising, but more studies are needed to draw valid conclusions.
Role of adenosine A2B receptor stimulation in ischaemic postconditioning: dawn of a new paradigm in cardioprotection: EXPERT'S PERSPECTIVE
Authors: K. Przyklenk
Journal: Cardiovascular Research (2012)

This editorial refers to an article by S. Philipp et al . [16][1] published in Cardiovascular Research in 2006. It is accompanied by a retrospective editorial by two authors of that original article, J.M. Downey and M.V. Cohen (doi:10.1093/cvr/CVS214), as part of this Spotlight on Landmark Papers in Cardiovascular Research . 

Adenosine has a long and storied history in the field of cardioprotection. A wealth of evidence accrued over three decades has demonstrated the ability of adenosine-based pharmacological strategies (and, in some instances, adenosine per se ) to attenuate multiple facets of myocardial ischaemia-reperfusion injury.1–15 It is equally well established that the favourable effects of adenosine and adenosine agonists are receptor-mediated and initiated by the stimulation of one or more of the family of four adenosine receptor subtypes (A1, A3, A2A, A2B; reviewed in1–3). Initial attention focused on the A1 subtype, with a host of studies reporting that pre-treatment with A1 receptor agonists significantly attenuated post-ischaemic contractile dysfunction and reduced the myocardial infarct size. Subsequent studies utilized both pharmacological and genetic approaches to interrogate the A1, A2A, and A3 receptors, and, in particular, the potential role of these receptor subtypes in the endogenous cardioprotection afforded by ischaemic preconditioning, postconditioning, and remote conditioning.1– …

 [1]: #ref-16
P16-specific DNA methylation by engineered zinc finger methyltransferase inactivates gene transcription and promotes cancer metastasis
Authors: Chenghua Cui, Ying Gan, Liankun Gu, James Wilson, Zhaojun Liu, Baozhen Zhang, Dajun Deng
Journal: Genome biology (2015)

P16 DNA methylation is well known to be the most frequent event in cancer development. It has been reported that genetic inactivation of P16 drives cancer growth and metastasis, however, whether P16 DNA methylation is truly a driver in cancer metastasis remains unknown. A P16-specific DNA methyltransferase (P16-dnmt) expression vector is designed using a P16 promoter-specific engineered zinc finger protein fused with the catalytic domain of dnmt3a. P16-dnmt transfection significantly decreases P16 promoter activity, induces complete methylation of P16 CpG islands, and inactivates P16 transcription in the HEK293T cell line. The P16-Dnmt coding fragment is integrated into an expression controllable vector and used to induce P16-specific DNA methylation in GES-1 and BGC823 cell lines. Transwell assays show enhanced migration and invasion of these cancer cells following P16-specific DNA methylation. Such effects are not observed in the P16 mutant A549 cell line. These results are confirmed using an experimental mouse pneumonic metastasis model. Moreover, enforced overexpression of P16 in these cells reverses the migration phenotype. Increased levels of RB phosphorylation and NFκB subunit P65 expression are also seen following P16-specific methylation and might further contribute to cancer metastasis. P16 methylation could directly inactivate gene transcription and drive cancer metastasis.
Prostate cancer mediates osteoclastogenesis through two different pathways
Authors: Hitoshi Inoue, Daizo Oka, Masahiro Shiba, Yasuyuki Arai, Masashi Nakayama, Kiyonori Shimizu, Kazuo Nishimura, Norio Nonomura, Akihiko Okuyama
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2924 

Genrally, prostatic cancer shows osteoblastic metastases, whereas the lesion also causes osteolysis. The present study was undertaken to test the effects of prostate cancer cell lines (LNCaP, DU145, PC3, and MDA PCa 2b) on osteoclastogenesis. Using a reverse transcription-polymerase chain reaction approach, we investigated the effects of crude conditioned medium (CM) obtained from prostate cancer cell lines on mRNA level of receptor activator of NF-κB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG) in mouse osteoblastic cell line, MC3T3-E1. Then we cocultured MC3T3-E1 with prostate cancer cell lines and evaluated mRNA level of RANKL and OPG in MC3T3-E1. Next, to investigate the effects on osteoclast precursor generated from mouse bone marrow treated with RANKL and MCSF, we cultured osteoclast precursor with crude CM obtained from prostate cancer cell lines in the presence or absence of RANKL or OPG. The number of multinucleated osteoclasts was evaluated by TRAP staining. Crude CM from all four prostate cancer cell lines enhanced expression of the mRNA for RANKL in MC3T3-E1; however, CM had no effect on expression of OPG mRNA. Coculture of MC3T3-E1 with prostate cancer cells yielded similar results. The number of mature osteoclasts induced by soluble RANKL increased significantly when osteoclast precursor cells were cultured with CM from LNCaP and DU145 cells. CM from LNCaP and DU145 cells also induced maturation from precursor in the absence of soluble RANKL, and this effect was not blocked by OPG. Our findings indicate that prostate cancer mediates osteoclastogenesis through induction of RANKL expression by osteoblasts and through direct actions on osteoclast precursors mediated by some factors other than RANKL.
MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin's disease in children: results of the Children's Cancer Group Phase III Trial.
Authors: R J Hutchinson, C J Fryer, P C Davis, J Nachman, M D Krailo, R T O'Brien, R D Collins, T Whalen, D Reardon, M E Trigg, G S Gilchrist
Journal: Journal of Clinical Oncology (1998)

PURPOSE A randomized trial designed to compare mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and daccarbazine (ABVD) (regimen A) with ABVD plus low-dose regional (extended-field) radiation therapy (EF RT) (regimen B) for the treatment of children and adolescents with stages III and IV Hodgkin's disease was conducted by the Children's Cancer Group (CCG-521) from 1986 until 1990. PATIENTS AND METHODS One hundred eleven eligible patients were randomized, 57 to regimen A and 54 to regimen B. All patients had pathologically verified stage III or stage IV Hodgkin's disease. RESULTS Overall survival (S) is 87% at 4 years and event-free survival (EFS) is 82%. Patients randomized to ABVD plus EF RT have a 4-year EFS of 87% compared with 77% for patients randomized to MOPP/ABVD (P = .09, two-sided). Patients randomized to ABVD plus EF RT have a 4-year S of 90% compared with 84% for patients randomized to MOPP/ABVD (P = .45, two-sided). Significant prognostic factors in multivariate analysis for EFS are stage of disease, erythrocyte sedimentation rate (ESR) at diagnosis, liver size at diagnosis, and, among stage III patients, the size of the mediastinal mass at diagnosis. The acute toxicities of treatment are largely hematopoietic in nature, whereas acute pulmonary and cardiac toxicities are modest and not limiting. CONCLUSION The results of this study show that, in advanced-stage Hodgkin's disease in children, equivalent results can be obtained by the addition of either MOPP or low-dose EF RT to the ABVD regimen; whether the addition of either contributes to outcome was not addressed in this study and will require additional testing. It is clear, however, that MOPP chemotherapy can safely be eliminated from front-line combination chemotherapy regimens for advanced Hodgkin's disease in pediatric patients.