tbuckley/cabot-search huggingface dataset:
Angiotensin II Type 2 Receptor Gene Deficiency Attenuates Susceptibility to Tobacco-Specific Nitrosamine-Induced Lung Tumorigenesis: Involvement of Transforming Growth Factor-β-Dependent Cell Growth Attenuation
Authors: Tsutomu Kanehira, Tatsuo Tani, Tetsuo Takagi, Yuichirou Nakano, Eric F. Howard, Masaaki Tamura
Journal: Cancer Research (2005)

Abstract To clarify an involvement of angiotensin II signaling in lung neoplasia, we have examined the effect of angiotensin II receptor deficiency on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)–induced lung tumorigenesis. Male angiotensin II type 2 receptor (AT2)-null mice with an SWR/J genetic background and control wild-type mice were treated with NNK (100 mg/kg, i.p.) or saline vehicle. NNK treatment caused the development of lung tumors in all wild-type control mice (100 % tumor prevalence), but only 85% of AT2-null mice developed tumors. The tumor multiplicity in AT2-null mice (1.9 ± 0.3) was significantly smaller than that in wild-type mice (4.1 ± 0.9). Primary cultured lung fibroblasts prepared from both AT2-null and wild-type mice markedly increased the colony counts of A549 lung cancer cells in soft agar, but a consistently higher colony count was observed with the wild-type fibroblasts (fold increase in colony number, 5.6 ± 0.5) than with the AT2-null fibroblasts (3.5 ± 0.8). The underlying mechanism by which angiotensin II regulates cancer cell growth is due to the regulation of active transforming growth factor-β (TGF-β) production. Although the total level of TGF-β was significantly stimulated when A549 cells were cocultured with either type of fibroblasts, the level of active TGF-β in the conditioned medium was consistently higher with AT2-null fibroblasts than with wild-type fibroblasts. These results imply that the AT2 receptor negatively regulates the level of active TGF-β and thus increases NNK-induced lung tumorigenesis. The AT2 receptor function in lung stromal fibroblasts may be a potential modulator of tumor susceptibility in chemical carcinogen-induced lung tumorigenesis.
Abstract 917: Post-treatment changes in levels of TNF family ligands and XIAP may predict sensitivity to IAP antagonist CUDC-427
Authors: Ruzanna Atoyan, Maria Elena S. Samson, Brianne Hantzis, Anna W. Ma, Ling Yin, Mylissa Borek, Steven Dellarocca, Brian Zifcak, Guangxin Xu, Jing Wang
Journal: Cancer Research (2014)

Abstract Inhibitors of apoptosis (IAP) proteins are a novel target for cancer therapy. Antagonists of IAP proteins have been shown to synergize with TNF receptor family signaling as well as with standard-of-care chemotherapeutics and targeted therapies. CUDC-427 is a potent, oral, monovalent IAP antagonist poised for more advanced clinical testing after completion of phase 1 trials using two different dosing schedules. Predictive biomarkers of response to CUDC-427 are expected to inform clinical development as monotherapy and in combination with other agents. In this study, we sought to identify potential markers of sensitivity to single-agent CUDC-427. Screening of more than 100 breast, ovarian and hematologic cancer cell lines using a viability assay identified several that are sensitive to CUDC-427 treatment. This sensitivity to CUDC-427 was associated with treatment-induced expression of TNFα or TRAIL in cell lines lacking basal levels of these TNF family ligands. In sensitive cell lines that express high basal levels of TNF family ligands prior to CUDC-427 treatment, induction of apoptosis was independent of NFκB signaling but dependent on caspase 8. Our results also confirmed that the addition of exogenous TNFα sensitized some but not all cell lines to CUDC-427 treatment, as previously reported by others. Interestingly, co-culture with stromal cells also sensitized certain hematologic cancer cell lines to CUDC-427 treatment. In addition, a decrease in XIAP levels was detected in cell lines that were highly sensitive to CUDC-427. These results suggest the potential for using TNF family ligand or XIAP levels pre- and post-treatment as predictive biomarkers of response to CUDC-427. Citation Format: Ruzanna Atoyan, Maria Elena S. Samson, Brianne Hantzis, Anna W. Ma, Ling Yin, Mylissa Borek, Steven Dellarocca, Brian Zifcak, Guangxin Xu, Jing Wang. Post-treatment changes in levels of TNF family ligands and XIAP may predict sensitivity to IAP antagonist CUDC-427. [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 917. doi:10.1158/1538-7445.AM2014-917
MECHANISM OF ACTION OF ACCELERANTS
Authors: N. H. CREASEY, A. C. ALLENBY, C. SCHOCK
Journal: British Journal of Dermatology (2006)

Summary.— Liquids such as dimethyl sulphoxide (DMSO), n‐decylamine or di‐2‐ethylhexylamine, which are able to accelerate the penetration through the skin of drugs dissolved in them, also cause varying degrees of inflammation and increased capillary permeability. The present work was undertaken to see whether the accelerant effect in vivo might be due partially to these circulatory changes. The accelerants studied produced effects in the rat which varied from increased capillary permeability disappearing within 1–5 h (xylene, DMSO, di‐2‐ethylhexylamine), to local circulatory arrest, marked inflammation and necrosis (n‐decylamine). The mild effects were less marked after the histamine (H) and 5‐hydroxy‐tryptamine (5HT) contents of the skin had been lowered by treatment with compound 48/80 and reserpine respectively. Thus, the mild effects appeared to be due to the local release of H and 5HT. The necrosis caused by n‐decylamine was not reduced by such procedures and was most likely due to its alkalinity and surface activity. Neither H, Trafuril nor any of the accelerants tested increased the clearance of intradermally‐injected radioactive 24Na, and those accelerants which produced necrosis caused a marked and rapid reduction of the skin clearance of 24Na. It was concluded that the accelerant effect in vivo was due not to increased capillary permeability or transport away from the skin but solely to the increased permeability of the stratum corneum.
Abstract 15993: Ablation of Phosphatase-1-Inhibitor-1 is Detrimental in CaMKII Overexpression Despite Reduction of SR Ca2+ Leak
Authors: Stefan Neef, Katrin Wittkopper, Christina Brammen, Thomas Sowa, Wolfram H Zimmermann, Joan Heller Brown, Lars S Maier, Ali El-Armouche
Journal: Circulation (2011)

Background: CaMKII is a central regulator of cardiac myocyte Ca2+ homeostasis. It is hyperactive in human heart failure (HF) and transgenic CaMKII overexpression leads to severe HF. Detrimental CaM...
Regulation of Crm1 expression in cancer cells
Authors: Pauline J. van der Watt, Virna D. Leaner
Journal: Clinical Cancer Research (2010)

Abstract Crm1 (or exportin 1) is a member of the karyopherin β protein family that mediates the nuclear export of cargo proteins and certain RNAs from the nucleus into the cytoplasm. We previously identified increased expression of Crm1 mRNA and protein in cervical tumours compared to normal epithelium, and increased Crm1 expression in transformed fibroblasts compared to normal fibroblasts. Moreover, Crm1 overexpression in cancer/transformed cells was found to be necessary for cell survival, implicating Crm1 as an attractive target for cancer therapy. We hypothesized that the increased expression of Crm1 in cancer/transformed cells derives from altered Crm1 promoter activity, yet no studies to date have investigated what regulates the Crm1 promoter. This study therefore set out to clone and characterize the Crm1 promoter. The cloned Crm1 promoter (-1405 to +99) was significantly more active in cancer and transformed cells compared to normal, correlating well with endogenous Crm1 protein levels. In order to define promoter regions responsible for the differential activity, deletion constructs were generated, and the −175 to +99 region was identified as important. Mutation of two CCAAT boxes and a GC box in this region significantly diminished Crm1 promoter activity in transformed and cancer cells, while having only a minor effect on Crm1 promoter activity in normal cells. In addition, ChIP assays revealed in vivo binding of NFY/CBP and Sp1 transcription factors to the CCAAT boxes and GC box of the Crm1 promoter in cancer and transformed cells, while binding was undetectable in normal cells. Interestingly, NFY and Sp1 expression levels were considerably elevated in transformed and cancer cells compared to normal. Taken together, we show that NFY- and Sp1-mediated activation of the Crm1 promoter contributes to Crm1 overexpression in cancer and transformed cells.
Abstract B93: A data base of N of 1 case reports from pancreatic cancer patients enrolled in First-in-man studies 2002 through 2012
Authors: Ignacio Garrido-Laguna, Danielle Tometich, Kenneth Boucher, Sunil Sharma
Journal: Cancer Research (2015)

Abstract Background: First-in-man (FIM) studies test different doses of novel therapeutics for the first time in humans. The purpose of this work was to develop a data base with FIM studies published in the last decade and to identify extraordinary responses to therapy in patients with advanced pancreatic cancer. Methods: We conducted a search in Scopus of all FIM studies published between 2002 and 2012. We collected the following information: author, date and journal of publication, class of drug, route of administration, dose escalation design, patient demographic information, grade 3-4 toxicities, dose limiting toxicities, deaths during trial (including treatment related deaths), radiologic response, trial location and tumor types included in each trial. Results: We identified 3065 references through the Scopus search. Among these we found 118 FIM studies enrolling 5369 patients with advanced cancers from 2002 through 2012. The most common tumor types were colorectal cancer 1055 (19.6%), lung cancer 456 (8.4%), melanoma 475 (8.8%), breast cancer 319 (5.9%) and pancreatic ductal adenocarcinoma 296 (5.5%). There were 194 deaths including 17 (0.3%) treatment related deaths. 12 patients (0.2%) had complete response as best response to therapy including a patient with pancreatic cancer treated with bosutinib (a novel Src/abl tyrosin kinase inhibitor). 1 patient with pancreatic cancer had partial response to CHR-3996 (a novel histone deacetylase inhibitor) with a progression free survival (PFS) of 12 months. A second patient had a partial response to trametinib (MEK inhibitor) with a PFS of 11.75 months. Interestingly histone deacetylases are components of core signaling pathways in pancreatic cancer such Cell cycle and Notch pathway. Moreover, Src is commonly activated in pancreatic cancer. Conclusions: Novel approaches are urgently needed to treat pancreatic cancer. This includes identifying novel treatment opportunities through N of 1 case reports. We have retrospectively identified extraordinary responses to therapy in patients with advanced pancreatic enrolled in FIM studies with Src, HDAC and MEK inhibitors. Efforts should be now focused on understanding the underpinning biology of the disease in these patients. Citation Format: Ignacio Garrido-Laguna, Danielle Tometich, Kenneth Boucher, Sunil Sharma. A data base of N of 1 case reports from pancreatic cancer patients enrolled in First-in-man studies 2002 through 2012. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B93.
Abstract 19209: Utilization of Inpatient Cardiac Rehabilitation During a Hospitalization for a Cardiac Condition: A National Sample
Authors: Quinn R Pack, Aruna Priya, Tara Lagu, Penny Pekow, Robert Berry, Auras R Atreya, Peter K Lindenauer
Journal: Circulation (2014)

Introduction: Inpatient cardiac rehabilitation (ICR) programs provide important services to patients, including daily ambulation, risk factor education, and coordinated referral to outpatient cardiac rehabilitation. However, little is known about national current utilization or practice patterns. Methods: Utilizing a geographically and structurally diverse sample of US hospitals (PREMIER data warehouse, Inc.) we examined the use of ICR using detailed administrative data from January 2007 to June 2011. Patients with an ICD-9 principal diagnosis of myocardial infarction (MI) or heart failure (HF), or with a procedure code for coronary artery bypass surgery (CABG), valve (V) surgery, or percutaneous coronary intervention (PCI) were included. Any patient with ≥ 1 service code for ICR was considered to have received ICR. Results: We evaluated 1,343,537 qualifying admissions from 458 hospitals. The overall ICR utilization rate was 20.8%. ICR utilization was highest in patients with surgical procedures with 45.5%, 37.0%, 40.7% for CABG, V, CABG+V, with rates of 23.7%, 31.3%, 23.7%, 15.6%, and 10.6% for elective PCI, urgent PCI, MI + PCI, MI alone, and HF respectively. Of 458 hospitals, 223 (49%) hospitals provided any ICR, with a median (10-90%) hospital ICR rate of 18.8% (0.06% - 74.1%). Hospitals in urban areas had significantly higher rates of ICR compared to hospitals in rural areas (30.1% vs. 18.6%) as did hospitals with presence of interventional services (surgical services: 31.5% vs. 20.2%, p = 0.006; PCI services: 30.3% vs. 14.7%, p =0.003). Conclusions: There appears to be substantial variation in the delivery of ICR across US hospitals. Less than half of hospitals with cardiac patients provide ICR and only a minority of patients ever receives ICR. This substantial gap in the secondary prevention of heart disease appears to warrant further investigation and intervention.
Abstract 1714: Erk inhibitor overcomes type II interleukin 1 receptor, a decoy receptor, associated Regorafenib resistance in colorectal carcinoma
Authors: Ai-Chung Mar, Chun-Ho Chu, Te-Chang Lee
Journal: Cancer Research (2014)

Abstract We have previously demonstrated that type II interleukin 1 receptor (IL1R2), which is an IL-1 decoy receptor and inhibits exogenous IL-1 signaling, activates the expression of several proinflammatory cytokines. We also found that enhanced expression of IL1R2 promotes tumor growth and increases tumor angiogenesis through activated IL-6/VEGF-A signalings. Recently, we observed a close association of enhanced expression of IL1R2 and Regorafenib resistance in colorectal cancer (CRC) cell lines. Regorafenib is the newly approved multi-kinase inhibitor used for treatment of late-stage metastatic CRC by US FDA. To have a better use of Regorafenib against CRC, we conducted experiments to understand the mechanism underlying which IL1R2 is involved in Regorafenib resistance. In the present study, we demonstrated that silencing of IL1R2 in HT29 cell overcame its resistance to Regorafenib whereas ectopic expression of IL1R2 decreased the sensitivity of HCT116 cell to Regorafenib in in vitro and in vivo systems. IL1R2 silencing also enhanced the apoptotic proteins expression in Regorafenib-treated cells. In addition, we have established Regorafenib-resistant DLD-1 colon cancer cells by growing them in the presence of Regorafenib. Consistently, higher IL1R2 expression was found in Regorafenib-resistant cells than the parental cells. Mechanistically, we observed that Regorafenib treatment significantly resulted in enhanced expression of extracellular-signal-regulated kinase (Erk), which functions as a survival factor, in IL1R2-overexpressing cells. Therefore, pretreatment of IL1R2-overepressing CRC cells with Erk inhibitor, U0126, reversed their Regorafenib resistance, suggesting that Erk signaling cascade is crucial in Regorafenib resistance resulted from IL1R2 overexpression. Taken together, our present study suggested that combination of Regorafenib and Erk inhibitor is a rationale regime to overcome IL1R2 overexpression-induced Regorafenib resistance in CRC patients, but also IL1R2 is a potential biomarker for colon cancer therapy. Citation Format: Ai-Chung Mar, Chun-Ho Chu, Te-Chang Lee. Erk inhibitor overcomes type II interleukin 1 receptor, a decoy receptor, associated Regorafenib resistance in colorectal carcinoma. [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 1714. doi:10.1158/1538-7445.AM2014-1714
Abstract 4095: The potential of PD-1/PD-L1 signaling inhibition outlined from clinical analysis of colorectal cancer
Authors: Tanja Grimmig, Romana Mönch, Andreas Rosenwald, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser
Journal: Cancer Research (2014)

Abstract Background: Recent data demonstrate the programmed death-1/programmed death ligand (PD-1/PD-L) pathway in T cell activation to play an important role in tumor evasion from host immunity. The aim of this study was to analyze the clinical significance of PD-1/PD-L1/L2 signaling in colorectal cancer (CRC). Methods: Gene and protein expression levels of PD-1, PD-L1, PD-L2, CD4, CD8 and Foxp3 were analyzed in tumors from patients with CRC (n=116 with completed 5-year follow up) by immunohistochemistry and RT-qPCR. Obtained data were analyzed for their prognostic significance with respect to outcome analysis. Results: 90.5% of the investigated tumors showed T cell infiltration, with 58% of the patients demonstrating PD-1-positive T cells in their tumors. Increased PD-L1-expression levels were found in patients who developed PD-1-positive T cell infiltration compared to PD-1-T cell negative individuals. Statistical analysis showed ligand expression (PD-L1/PD-L2) in the cancer tissues combined with dense PD-1-positive T cell infiltration to be associated with poor prognosis in affected patients (p&amp;lt;0.001). Multivariate analysis demonstrated PD-L expression in the tumors to be an independent prognostic factor in CRC. Conclusion: The presented results from clinical cancers suggest for the first time for CRC that negative signaling of infiltrating PD-1-positive T cells through PD-L1 expression within the tumor is promoting tumor progression through downregulation of anti-tumor immunity. In conclusion, this study demonstrates the importance of strategies inhibiting negative PD-1/PD-L1 signaling in CRC. Citation Format: Tanja Grimmig, Romana Mönch, Andreas Rosenwald, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser. The potential of PD-1/PD-L1 signaling inhibition outlined from clinical analysis of colorectal cancer. [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 4095. doi:10.1158/1538-7445.AM2014-4095
Genitoperineal papular acantholytic dyskeratosis is allelic to Hailey-Hailey disease
Authors: C. Pernet, D. Bessis, M. Savignac, E. Tron, B. Guillot, A. Hovnanian
Journal: British Journal of Dermatology (2012)

Journal Article Genitoperineal papular acantholytic dyskeratosis is allelic to Hailey–Hailey disease Get access C. Pernet, C. Pernet Department of Dermatology, St Eloi Hospital, 80 avenue A. Fliche, 34295 Montpellier Cedex 5, FranceUniversity of Montpellier I, Montpellier, France Search for other works by this author on: Oxford Academic Google Scholar D. Bessis, D. Bessis Department of Dermatology, St Eloi Hospital, 80 avenue A. Fliche, 34295 Montpellier Cedex 5, FranceUniversity of Montpellier I, Montpellier, FranceINSERM U1058, Montpellier, France Search for other works by this author on: Oxford Academic Google Scholar M. Savignac, M. Savignac INSERM U563, Toulouse, F‐31300 France Search for other works by this author on: Oxford Academic Google Scholar E. Tron, E. Tron Departments of Genetics and Dermatology, Necker Hospital for Sick Children, 149 rue de Sèvres, 75743 Paris Cedex 15, France Search for other works by this author on: Oxford Academic Google Scholar B. Guillot, B. Guillot Department of Dermatology, St Eloi Hospital, 80 avenue A. Fliche, 34295 Montpellier Cedex 5, FranceUniversity of Montpellier I, Montpellier, FranceINSERM U1058, Montpellier, France Search for other works by this author on: Oxford Academic Google Scholar A. Hovnanian A. Hovnanian Departments of Genetics and Dermatology, Necker Hospital for Sick Children, 149 rue de Sèvres, 75743 Paris Cedex 15, FranceINSERM U781, Paris, F‐75015 FranceUniversity Paris V René Descartes, Paris, F‐75015 France Alain Hovnanian. E‐mail: alain.hovnanian@inserm.fr Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 167, Issue 1, 1 July 2012, Pages 210–212, https://doi.org/10.1111/j.1365-2133.2012.10810.x Published: 01 July 2012
Activation and resolution of periodontal inflammation and its systemic impact
Authors: Hatice Hasturk, Alpdogan Kantarci
Journal: Periodontology 2000 (2015)

Abstract Inflammation is a highly organized event impacting upon organs, tissues and biological systems. Periodontal diseases are characterized by dysregulation or dysfunction of resolution pathways of inflammation that results in failure to heal and in a dominant chronic, progressive, destructive and predominantly unresolved inflammation. The biological consequences of inflammatory processes may be independent of the etiological agents, such as trauma, microbial organisms and stress. The impact of the inflammatory pathological process depends upon the tissues or organ system affected. Whilst mediators are similar, there is tissue specificity for the inflammatory events. It is plausible that inflammatory processes in one organ could directly lead to pathologies in another organ or tissue. Communication between distant parts of the body and their inflammatory status is also mediated by common signaling mechanisms mediated via cells and soluble mediators. This review focuses on periodontal inflammation, its systemic associations and advances in therapeutic approaches based on mediators acting through orchestration of natural pathways to resolution of inflammation. We also discuss a new treatment concept in which natural pathways of resolution of periodontal inflammation can be used to limit systemic inflammation and promote healing and regeneration.
UK government announces review of selection process for junior doctors
Authors: Rebecca Coombes
Journal: BMJ (2007)

The UK government has launched an urgent review of the beleaguered specialist training scheme, but says that the first round of interviews must stand.

The Department of Health backed down this week in the face of intense criticism of the new scheme, the medical training application system (MTAS). Serious flaws in the new online system have led to mass disquiet among junior doctors and consultants alike. 

Complaints about the procedure include the fact that the online system has been blighted by technical problems, the application process was confusing, and the selection procedure was thought by many to be unfair, with many highly qualified candidates being rejected.

After a crisis meeting with the royal colleges and the BMA last week, the health …
Transcatheter Aortic Valve Replacement in Europe
Authors: Darren Mylotte, Ruben L.J. Osnabrugge, Stephan Windecker, Thierry Lefèvre, Peter de Jaegere, Raban Jeger, Peter Wenaweser, Francesco Maisano, Neil Moat, Lars Søndergaard, Johan Bosmans, Rui C. Teles, Giuseppe Martucci, Ganesh Manoharan, Eulogio Garcia, Nicolas M. Van Mieghem, A. Pieter Kappetein, Patrick W. Serruys, Ruediger Lange, Nicolo Piazza
Journal: Journal of the American College of Cardiology (2013)
Europe plans tighter controls on breast implants
Authors: Rory Watson
Journal: BMJ (2001)

Tighter controls on breast implant operations are being planned by the European Commission to protect the health and safety of patients.

The initiative is being taken after a lengthy campaign by the Silicone Support UK group and the European parliament to persuade European and national authorities to enforce stricter standards on cosmetic surgery operations.

Erkki Liikanen, the enterprise commissioner, told MEPs last week that he intends to use existing EU legislation on medical devices to …