tbuckley/cabot-search huggingface dataset:
Abstract 4526: BIBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models of sarcoma
Authors: Parag P. Patwardhan, Elgilda Musi, Kathryn S. Ivy, Natalie Giovino, Gary K. Schwartz
Journal: Cancer Research (2014)

Abstract BIBF1120 (Nintedanib), an investigational potent small molecule angiokinase inhibitor, selectively binds to and blocks receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor, (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR). Nintedanib has shown promising results in preclinical as well as clinical studies of non-small cell lung cancer, colorectal, ovarian cancer and other solid tumors. We tested the in vitro anti-proliferative activity of BIBF1120 in a panel of sarcoma cell lines including malignant peripheral nerve sheath tumor (MPNST), synovial (SYO-I), Ewing's (CHP100), osteo (SaOS2) and liposarcoma (LS141). Our results indicate that when compared to other potent RTK inhibitors such as Imatinib and Pazopanib, BIBF1120 is highly efficient at nanomolar to low micromolar concentrations in blocking proliferative activity of sarcoma cell lines, specifically, SYO-I and MPNST, which are highly dependent on PDGFR signaling. Western blot analysis to test the efficacy of BIBF1120 confirmed significant blockade of RTK signaling pathways. Ras activation and/or activation of mitogen activated protein kinase (MAPK) pathway has been shown to be critical in sarcomas including MPNST and synovial sarcomas. Unlike Imatinib and Pazopanib, BIBF1120 also blocked MAPK signaling pathway as demonstrated by p-ERK1/2 blockade. In addition to the RTKs, mTOR (mammalian Target of Rapamycin) protein plays a key role in AKT activation and downstream survival signaling. Combination of RTK blockade by BIBF1120 and mTOR blockade by TORC1 inhibitor rapamycin resulted in significantly stronger inhibition of in vitro cellular proliferation compared to single agent treatments. Taken together, our data strongly supports further clinical research of BIBF1120 in sarcoma. Combining potent inhibitors of tyrosine kinase signaling, MAPK signaling and inhibitors of mTOR pathway such as rapamycin could provide a new therapeutic approach in this disease. Citation Format: Parag P. Patwardhan, Elgilda Musi, Kathryn S. Ivy, Natalie Giovino, Gary K. Schwartz. BIBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models of sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4526. doi:10.1158/1538-7445.AM2014-4526
Inactivation of Factor XIa by Plasma Protease Inhibitors
Authors: Cheryl F. Scott, Marc Schapira, Harold L. James, Allen B. Cohen, Robert W. Colman
Journal: Journal of Clinical Investigation (1982)

Factor XIa is a plasma protease that, by activating Factor IX, plays an important role in the early phase of the intrinsic pathway of blood coagulation. Four plasma protease inhibitors, alpha(1)-protease inhibitor, antithrombin III, C1-inhibitor, and alpha(2)-plasmin inhibitor, have been reported to inactivate human Factor XIa, but their quantitative contribution to the inactivation of Factor XIa in plasma has not been fully assessed. Using purified systems, we observed that the second-order rate constants for the reaction of Factor XIa with alpha(1)-protease inhibitor, antithrombin III, and CI-inhibitor were 4.08, 10, and 14.6 M(-1) min(-1) x 10(3), respectively. The pseudo-first-order rate constants, at plasma concentration of the inhibitors, were 1.86 x 10(-1), 4.68 x 10(-2), and 2.4 x 10(-2) min(-1), respectively. These kinetic data predict that alpha(1)-protease inhibitor should account for 68%, antithrombin III for 16%, and C1-inhibitor and the equipotent alpha(2)-plasmin inhibitor each for 8% of the total inhibitory activity of plasma against Factor XIa. The rate of inactivation of Factor XIa in various plasma samples specifically deficient in inhibitors was consistent with these predictions. Factor XI, the zymogen form of Factor XIa, circulates in plasma associated with the contact system cofactor, high molecular weight kininogen (HMW kininogen). Kinetic analysis indicated the existence of a reversible bimolecular Factor XIa-HMW kininogen complex with a dissociation constant (K(d)) = 0.17 muM. The light chain derived from HMW kininogen decreased the inactivation rate of Factor XIa by C1-inhibitor with a K(d) of 0.08 muM for a complex of Factor XIa and the light chain derived from HMW kininogen. The protective effect of HMW kininogen was confirmed by the finding that the inactivation rate of Factor XIa in kininogen-deficient plasma was increased over normal plasma. The present study confirms that alpha(1)-protease inhibitor is the major inhibitor of Factor XIa in plasma, and that the formation of a reversible complex between Factor XIa and HMW kininogen decreases the rate of inactivation of the enzyme by its inhibitors.
Treatment of preclinical asthma or chronic obstructive pulmonary disease (COPD) with inhaled steroids in the 'DIMCA' project (an early detection, monitoring and intervention program in asthma and COPD): acceptable compliance rates
Authors: P.M. van Grunsven, C.P. van Schayck, J. Molema, R.P. Akkermans, C. van Weel
Journal: American Journal of Respiratory and Critical Care Medicine (1997)
Chlorozotocin
Authors: Lawrence C. Panasci, Dianna Green, Philip S. Schein
Journal: Journal of Clinical Investigation (1979)

Chlorozotocin is a chloroethyl nitrosourea with a glucose carrier that has curative activity for the murine L1210 leukemia, but is nonmyelosuppressive in mice. To determine the mechanism for this unique property of reduced bone marrow toxicity, comparative studies were conducted with chlorozotocin and CCNU, a myelotoxic chloroethyl nitrosourea.
Abstract 3650: PI3-kinase gamma controls the macrophage M1-M2 switch, thereby promoting tumor immunosuppression and progression
Authors: Megan Kaneda, Sara Gorjestani, Judith A. Varner
Journal: Cancer Research (2014)

Abstract Innate immune cells (macrophages, monocytes and neutrophils) rapidly migrate to sites of tissue damage where they initially activate T cells (M1 classical response). These cells gradually transition to suppress T cell responses, while stimulating wound healing (M2 alternative response). In tumors, however, the normal immune response is chronically disrupted and an exaggerated immunosuppressive, wound healing, tumor-promoting (M2) response prevails. In order to identify the mechanisms regulating this M2 response in tumor inflammation and to develop novel therapeutics to control it, we set out to explore the role of macrophage signaling in control of the M1-M2 switch. Using RNA seq analysis of gene expression patterns in M1 and M2 macrophages in vitro and gene expression analysis of myeloid cells in spontaneous and orthotopic mouse models of lung, pancreatic and breast cancer, we found that myeloid cell PI3Kinase gamma controls the switch between the M1-M2 phenotype in human and murine macrophages. PI3Kinase gamma signaling stimulates an immunosuppressive, wound healing gene expression program exemplified by expression of immunosuppressive and pro-angiogenic factors, such as Arginase1, TGFbeta1, PDGFBB, MMP9, and MMP13, and suppression of pro-inflammatory factors such as IL12, iNos, and interferon gamma. Blockade of this pathway by genetic or pharmacological inhibition of PI3Kgamma blocks this immunosuppressive, wound healing gene expression program and stimulates instead a T cell activating gene expression program as well as T cell mediated tumor cell killing. PI3Kgamma blockade inhibits tumor growth and metastasis in mouse models of lung, pancreatic and breast carcinoma. Our studies demonstrate the critical role of PI3Kgamma signaling in the control of the M1-M2 macrophage switch and demonstrate that this kinase is an important therapeutic target to suppress tumor growth by targeting inflammation that is associated with all solid tumors. Citation Format: Megan Kaneda, Sara Gorjestani, Judith A. Varner. PI3-kinase gamma controls the macrophage M1-M2 switch, thereby promoting tumor immunosuppression and progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3650. doi:10.1158/1538-7445.AM2014-3650
A Research Agenda for Malaria Eradication: Vaccines
Journal: PLoS Medicine (2011)

Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented.
Science commentary: Extracorporeal membrane oxygenation
Authors: A. Berger
Journal: BMJ (1998)

Extracorporeal membrane oxygenation is a technique for oxygenating blood outside the body which does away with the need for gas exchange inside the lungs. It is an offshoot of cardiopulmonary bypass technology but does not require the body to be cooled down first and requires minimal heparin. This
Fortnightly review: Controversial aspects of thyroid disease
Authors: F W F Hanna, J H Lazarus, M F Scanlon
Journal: BMJ (1999)

The thyroid gland controls the metabolic rate of many organs and tissues Underactivity and overactivity of thyroid function represent the commonest endocrine problems, have widespread manifestations, and often require long term treatment. Therefore, all practising clinicians have to be aware of thyroid physiology and the consequences of dysthyroidism.

#### Summary points

Simplifying the treatment regimen for thyroid disease is the most important way of improving patient compliance

All solitary thyroid nodules should be examined by fine needle aspiration; the technique may also be helpful in multinodular goitres if carcinoma is suspected

Subclinical hyperthyroidism is defined as suppressed concentrations of thyroid stimulating hormone with normal serum thyroxine and triiodothyronine concentrations

In subclinical hyperthyroidism the incidence of atrial fibrillation increases as thyroid stimulating hormone concentrations decrease, and in postmenopausal women bone mineral density may also be slightly reduced

Smoking increases the risk of both Graves' disease and Graves' ophthalmopathy

We have chosen topics in thyroid disease of interest to clinicians in both primary and secondary care: compliance, because it remains a challenge to all clinicians; and subclinical thyroid disease and the effect of amiodarone on thyroid function because they are interesting and evolving topics. We have also addressed some aspects of Graves' disease that have recently generated interest. Our sources included papers from Medline as well as discussions from recent national and international endocrinology meetings.

### Box 1 —Causes of increased thyroid stimulating hormone concentrations with adequate thyroxine replacement dose

#### Reduced absorption

Sucralfate

Cholestyramine

Ferrous sulphate

Aluminium hydroxide

#### Reduced conversion of thyroxine to triiodothyronine

Amiodarone

Management of thyroid disorders usually requires prolonged, and often lifelong, courses of treatment. Hence adequate compliance is needed to achieve and maintain euthyroidism. The sensitive assay for thyroid stimulating hormone has advantages over assays for thyroxine, triiodothyronine, and free thyroxine, and both the free thyroxine index and older versions of the thyroid stimulating hormone radioimmunoassay. The sensitive assay helps to differentiate normal concentrations of thyroid stimulating …
To My Husband
Authors: Mary R. Tanner
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 4401: A novel drug suppresses proliferation of lung cancer cells via increasing the CBL activity and down-regulating epidermal growth factor receptor
Authors: Kuo-Yen Huang, Szu-Hua Pan, Wen-Lung Wang, Ching-Shih Chen, Tse-Ming Hong, Pan-Chyr Yang
Journal: Cancer Research (2014)

Abstract Aberrant epidermal growth factor receptor (EGFR) signaling is one of the most critical oncogenic pathways in NSCLC that may trigger the tumor progression. Thus, how to suppress the EGFR downstream signaling cascade or to reduce the EGFR expression level has long been considered an important therapeutic approach for cancer interventions. Here, we found a regulatory mechanism by which the degradation of EGFR is enhanced by a novel promising drug, compound 22. First, the exposure to compound 22 induced cell death via apoptosis in lung cancer cell lines, including EGFR wild type A549 as well as EGFR mutant PC9 and H1975 cells. Compound 22 decreased the EGFR protein level in a dose-dependent manner and facilitated dephosphorylation of its downstream targets, including AKT and ERK, both of which play a critical role for cancer cell survival. Second, we observed that compound 22 induced EGFR degradation through proteasome degradation in the cycloheximide chase plus MG132 assay. Additionally, compound 22 increased the CBL (the ubiquitin E3 ligase)-mediated ubiquitination of EGFR, which was accompanied by the enhancement of Y1045 phosphorylation in the EGFR kinase domain. Overall, these pieces of evidence suggest that compound 22 is a novel class of anticancer drug which is able to inhibit the TKI-resistant NSCLC cells by inducing the degradation of EGFR. Citation Format: Kuo-Yen Huang, Szu-Hua Pan, Wen-Lung Wang, Ching-Shih Chen, Tse-Ming Hong, Pan-Chyr Yang. A novel drug suppresses proliferation of lung cancer cells via increasing the CBL activity and down-regulating epidermal growth factor receptor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4401. doi:10.1158/1538-7445.AM2014-4401
Abstract 4036: Optimal Phase Relationship between Defibrillation and Mechanical Chest Compressions Improves Shock Success
Authors: Yongqin Li, Hao Wang, Jun Hwi Cho, Weilun Quan, Gary Freeman, Joe Bisera, Max Harry Weil, Wanchun Tang
Journal: Circulation (2008)

Introduction  A newly developed blanket provides the protection for rescuer from shock during cardiopulmonary resuscitation (CPR) and allow for uninterrupted chest compression. We examined relationships between the phase of manual compression and the timing of defibrillation based on measurement of the 50% defibrillation threshold (DFT50).   Methods  Ventricular fibrillation (VF) was electrically induced and untreated for 10 seconds in 8 domestic male pigs weighing between 22–31 kg. The depth and frequency of manual chest compression utilizing the isolated blanket initiated and continued for 25 seconds guided by a CPR prompter (iCPR, ZOLL Medical Corporation, Chelmsford, MA). A biphasic electrical shock of variable energies ranging from 30~150J was delivered at 5 phases of the compression period as shown in Figure 1–A. A group in which defibrillation was attempted at a constant 2 seconds following discontinued of chest compression served as a control.   Results  No difference between coronary perfusion pressures (CPP) prior to delivering of the shock were observed between the 6 groups. The calculated energy required for defibrillation, however, was significantly lower during the latter half of decompression as represented by group C and D (Figure 1–B).   Conclusion  Defibrillation efficacy is maximal when an electrical shock is delivered during the latter phase of decompression.
Abstract 13349: Long Term (4 Years) Clinical and Echocardiographic Results of Transcatheter Self-expanding Medtronic Corevalve Device in Patients With Aortic Stenosis
Authors: Vassilis Voudris, Sofia Thomopoulou, Manolis Vavuranakis, Maria Kariori, Christos Stefopoulos, George Karavolias, Carmen Moldovan, Efthychia Sbarouni, Marina Balanika, Mazen Khouri, Christodoulos Stefanadis
Journal: Circulation (2014)

Introduction: Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement for patients (pts) with severe aortic stenosis considered inoperable or at high operative risk. However, little is known about long-term outcomes following TAVI. In this study we assessed the 4-year clinical and echocardiographic outcomes of pts undergoing TAVI with the self expanding Medtronic CoreValve prosthesis. Methods: The 4-year outcomes following successful TAVI with the self-expanding aortic valve device (Medtronic CoreValve) were evaluated in 60 pts (mean age 79+6 years, male 47 %, Logistic Euroscore 28.43+10.93%). Principal outcome measures were death from any cause. An echocardiograpic examination was performed at prespecified intervals of 6 and 12 months, and every year afterwards. Categorical variables were compared using X2 test, and continuous variables using t test. Survival curves were also constructed. Results: All cause mortality at 1, 2, 3, and 4 years was 16.7%, 28.3%, 30%, and 40% respectively. Mean aortic valve gradient decreased from 50.96+18.6 mm Hg pre to 9.22+ 4.6 mm Hg after TAVI (P&lt;0.001) and remained at 15.69+6.3 mm Hg at 4 years (p for post-TAVI trend &lt;0.01). Mean aortic valve area increased from 0.66+ 0.14 cm2 pre to 1.87+0.33 cm2 after TAVI (p&lt;0.001) and remained at 1.23+ 0.25 cm2 at 4 years (p for post-TAVI trend &lt;0.01). Paravalvular leak (minimal to moderate) was observed in 61% of pts post-TAVI; however, there was no case of progression to severe regurgitation at 4 years follow-up. Conclusions: TAVI with the Medtronic CoreValve prosthesis is associated with sustained clinical and functional cardiovascular benefits in inoperable or high-risk patients with symptomatic aortic stenosis up to 4-year follow-up.
Abstract 3745: Optimization of an assay for the detection of phosphorylated FAK by immunohistochemistry in formalin-fixed, paraffin-embedded human tissue and cell lines
Authors: Lisa M. Dauffenbach, Gela C. Sia, Patricia A. Cash, Sherif K. Girees, Ryan S. Lim, Jianping Zheng, Eric P. Olsen, Rana Richeh, Christopher A. Kerfoot
Journal: Cancer Research (2014)

Abstract Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase with elevated expression in most human cancers, most notably in invasive metastasis. FAK is involved in cell adhesion, motility, and apoptosis, and it is a target for oncology therapeutics. FAK activation occurs by phosphorylation at Tyr397 in response to integrin clustering caused by cell adhesion. The development of a sensitive and specific immunohistochemical assay for phosphorylated FAK (pFAK) is important for pharmacodynamic biomarker studies. The purpose of this study was to investigate 4 commercially available anti-pFAK antibodies in human tissues and cell lines. Antibodies included 3 rabbit monoclonals (EP2160Y, 141-9, and 31H5L17) and 1 rabbit polyclonal. Antibody specificity was evaluated in a variety of cell lines (BxPC3, HCT-116, LOVO, MDA-MB-231, and MiaPaca2) treated with 2 FAK inhibitors: TAE226 (NVP-TAE226) and PF-562271. Decreased immunohistochemical staining for pFAK was observed in post-treatment samples of cell lines with baseline pFAK expression. TAE226 was more potent at inhibiting pFAK staining. Membrane staining was observed with the rabbit polyclonal and rabbit clone EP2160Y only. Each of the 4 antibodies was tested in human breast cancer tissues using tissue microarrays created by Mosaic Laboratories. The percentage of breast cancer samples that were pFAK positive was 96% with clone EP2160Y, 83% with clone 141-9, 92% with clone 31H5L17 and 96% with the polyclonal. The percentage of cells that were positive within each breast cancer sample ranged from 63% to 83%, depending on the antibody used (standard deviations between 30% and 44%). Immunohistochemistry with the polyclonal and clone EP2160Y antibodies demonstrated membrane and cytoplasmic staining, while clones 141-9 and 31H5L17 demonstrated primarily cytoplasmic staining. Based on reduction of pFAK staining in treated cells and acceptable performance in human cancer tissues, pFAK immunohistochemistry is “fit for purpose” for evaluation of FAK inhibitor activity in pre- and post-treatment clinical trial tissue biopsies. Citation Format: Lisa M. Dauffenbach, Gela C. Sia, Patricia A. Cash, Sherif K. Girees, Ryan S. Lim, Jianping Zheng, Eric P. Olsen, Rana Richeh, Christopher A. Kerfoot. Optimization of an assay for the detection of phosphorylated FAK by immunohistochemistry in formalin-fixed, paraffin-embedded human tissue and cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3745. doi:10.1158/1538-7445.AM2014-3745
The criminality of the mentally ill: a dangerous misconception
Authors: Linda A. Teplin
Journal: American Journal of Psychiatry (1985)

A longstanding controversy is the relative dangerousness and criminality of the mentally ill. The author presents observational data from 1,072 police-citizen encounters in an urban area. The data show that persons exhibiting signs of serious mental disorder were not suspected of serious crimes at a rate disproportionate to their numbers in the population. The patterns of crime for mentally disordered persons and for non-mentally-disordered persons were substantially similar. These data help dispel the myth that the mentally ill constitute a dangerous group prone to violent crime.