tbuckley/cabot-search huggingface dataset:
Imatinib Mesylate Efficiently Achieves Therapeutic Intratumor Concentrations <b> <i>in Vivo</i> </b> but Has Limited Activity in a Xenograft Model of Small Cell Lung Cancer
Authors: Nicholas C. Wolff, Dwight E. Randle, Merrill J. Egorin, John D. Minna, Robert L. Ilaria
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Despite recent advances in cancer therapy, long-term survival in small cell lung cancer (SCLC) remains uncommon, underscoring the need for novel therapeutic approaches. Previous studies have identified constitutive expression of the receptor tyrosine kinase, c-Kit, and its ligand, stem cell factor, in a substantial proportion of SCLC specimens. The purpose of this study was to determine whether imatinib mesylate, an inhibitor of c-Kit, could achieve therapeutic concentrations in tumors and in brain (a frequent site of SCLC metastasis) and interfere with SCLC tumor growth in vivo. Experimental Design: Human SCLC tumor cell lines with constitutive c-kit expression and tyrosine phosphorylation (NCI-H209, NCI-H526, and NCI-H1607) were used to establish SCLC tumor xenografts in NCr nude (nu/nu)-immunodeficient mice. SCLC tumor-bearing mice were randomly assigned to imatinib or control (water) administered twice a day by oral gavage. Imatinib concentrations in plasma, brain, and tumor were quantitated and correlated with tumor response. Results: Therapeutic concentrations of imatinib were achieved in plasma and tumor xenografts but not in the brain. Imatinib blocked the constitutive activation of c-kit in SCLC tumor cell lines in vitro but had a negligible effect on SCLC xenograft growth in vivo. Conclusions: Orally administered imatinib rapidly reaches therapeutic concentrations in SCLC xenografts, suggesting the feasibility of combining imatinib with other novel or traditional chemotherapeutic agents in SCLC or other solid tumors. The c-Kit signaling pathway does not appear to play a critical role in SCLC proliferation and viability in vivo, however, suggesting that imatinib is unlikely to be effective as monotherapy for SCLC.
Ets-1 is a negative regulator of Th17 differentiation
Authors: Jacques Moisan, Roland Grenningloh, Estelle Bettelli, Mohamed Oukka, I-Cheng Ho
Journal: The Journal of Experimental Medicine (2007)

IL-17 is a proinflammatory cytokine that plays a role in the clearance of extracellular bacteria and contributes to the pathology of many autoimmune and allergic conditions. IL-17 is produced mainly by a newly characterized subset of T helper (Th) cells termed Th17. Although the role of Th17 cells in the pathology of autoimmune diseases is well established, the transcription factors regulating the differentiation of Th17 cells remain poorly characterized. We report that Ets-1–deficient Th cells differentiated more efficiently to Th17 cells than wild-type cells. This was attributed to both low IL-2 production and increased resistance to the inhibitory effect of IL-2 on Th17 differentiation. The resistance to IL-2 suppression was caused by a defect downstream of STAT5 phosphorylation, but was not caused by a difference in the level of RORγt. Furthermore, Ets-1–deficient mice contained an abnormally high level of IL-17 transcripts in their lungs and exhibited increased mucus production by airway epithelial cells in an IL-17–dependent manner. Based on these observations, we report that Ets-1 is a negative regulator of Th17 differentiation.
Nobel Lectures: Physiology or Medicine 1996-2000
Authors: Patrick Vallance
Journal: Journal of the Royal Society of Medicine (2004)

No prize for science carries as much cachet as the Nobel. Everyone has heard of it and small children dream that one day they may win it. Many of the major discoveries that have changed the way we practise medicine have been rewarded with the prize in Physiology or Medicine. Banting for the discovery of insulin (1923), Einthoven for the ECG (1924), Landsteiner for the discovery of blood groups (1930), Fleming, Chain and Florey for penicillin (1945), Cournand, Forssmann and Richards for cardiac catheterization (1956), Watson, Crick and Wilkins of course (1962), Cormack and Hounsfield for CT scanning (1979), Jim Black for his discovery of beta-blockers and H2 antagonists (1988) and John Vane for his work on aspirin and prostaglandins (1982). Others in retrospect, seem less obvious—Wagner-Jauregg's discovery of ‘the therapeutic value of malaria inoculation in the treatment of dementia paralytica’ or Grib Fibiger for ‘his discovery of the Spiroptera Carcinoma’. What is surprising is that despite the prize's importance to medicine and our work as doctors, and the huge publicity it receives each year, my questioning of a semi-random selection of medical students and junior doctors suggests that few are able to name the winners, identify discoveries that won the prize or put an approximate date to even the most famous of the discoveries. We forget where our profession owes its greatest debts.

The book of Nobel Lectures (1996-2000) edited by Hans Jornvall is a joy. These are personal essays giving insight into the lives, careers and minds of Nobel winners. The reader can't help but try to identify the common strands—what makes a Nobel Laureate, what motivates them, which paths do they follow, and what part does luck play in the process of their discoveries? One thing we do know is that there are dynasties, with Nobel winners tending to beget other winners, or at least pedigrees of high-flying scientists connected through common laboratories. The beauty of scientific work of this calibre is often the simplicity of the questions: we know that proteins are being made all the time, how do they get to where they need to be (Blobel 1999); or why does acetylcholine relax blood vessels in an animal but not when you take the blood vessel out (Furchgott 1998)? Reading one or two of the Nobel Lectures seems to me a vital part of a doctor's training. To get a broader scope than the few lectures presented in this book, a visit to the Nobel website [http://www.nobel.se/] is worthwhile. This also gives you an opportunity to see whether you think you can spot which Nobel Prize discoveries are going to change the world, which are going to be forgotten, and which may even prove to be wrong in 50 years' time.
Testing Women With Endometrial Cancer to Detect Lynch Syndrome
Authors: Janice S. Kwon, Jenna L. Scott, C. Blake Gilks, Molly S. Daniels, Charlotte C. Sun, Karen H. Lu
Journal: Journal of Clinical Oncology (2011)

Women with endometrial cancer as a result of Lynch syndrome may not be identified as such by Amsterdam II criteria. We estimated the costs and benefits of different testing criteria to identify Lynch syndrome in women with endometrial cancer.
COMP–Angiopoietin-1 Ameliorates Renal Fibrosis in a Unilateral Ureteral Obstruction Model
Authors: Won Kim, Sang-Ok Moon, Sang Yong Lee, Kyu Yun Jang, Chung-Hyun Cho, Gou Young Koh, Kyu-Sil Choi, Kwon-Ha Yoon, Mi Jeong Sung, Duk Hoon Kim, Sik Lee, Kyung Pyo Kang, Sung Kwang Park
Journal: Journal of the American Society of Nephrology (2006)

Injury to the renal microvasculature may be a major factor in the progression of renal disease; therefore, protection of endothelial cells (EC) in renal vasculature may have a therapeutic role in renal fibrosis. Recently, a soluble, stable, and potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, was developed. The contribution of COMP-Ang1 in renal interstitial fibrosis, however, remains to be clarified. This study investigated the effects of COMP-Ang1 on peritubular capillary EC in the renal cortex and the renal fibrogenic process that is triggered by unilateral ureteral obstruction. COMP-Ang1 preserved renal platelet-EC adhesion molecule-1–and Tie2-positive EC. Morphologic examination indicated less tubular injury and tubulointerstitial fibrosis in mice that received COMP-Ang1 than vehicle-treated mice. Interstitial type I collagen and myofibroblast accumulation were significantly suppressed by COMP-Ang1 treatment. COMP-Ang1 increased Tie2 and Akt phosphorylation in ureteral obstructed kidneys. Renal surface microvasculature and renal blood flow were higher after treatment with COMP-Ang1 than with vehicle. COMP-Ang1 treatment decreased monocyte/macrophage infiltration, tissue levels of TGF-β1, and Smad 2/3 phosphorylation and increased Smad 7 in the obstructed kidney. These results demonstrate that COMP-Ang1 treatment can decrease the progression of renal fibrosis in unilateral ureteral obstruction. COMP-Ang1 may be an endothelium-specific therapeutic modality in fibrotic renal disease.
Contact urticaria and anaphylactoid reaction induced by topical application of nitrogen mustard
Authors: EVA GRUNNET
Journal: British Journal of Dermatology (1976)

Journal Article Contact urticaria and anaphylactoid reaction induced by topical application of nitrogen mustard Get access EVA GRUNNET EVA GRUNNET Department of Dermatology, Marselisborg Hospital, University of Aarhus, Aarhus, Denmark Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 94, Issue 1, 1 January 1976, Pages 101–103, https://doi.org/10.1111/j.1365-2133.1976.tb04350.x Published: 01 January 1976
Lack of immune deficiency in sarcoidosis: compartmentalisation of the immune response.
Authors: B N Hudspith, K C Flint, D Geraint-James, J Brostoff, N M Johnson
Journal: Thorax (1987)

The original findings of peripheral anergy in sarcoidosis led to the conclusion that sarcoidosis was a disease associated with immune deficiency, but patients with sarcoidosis do not appear to suffer from repeated infections suggestive of immune suppression. With the technique of bronchoalveolar lavage it is now possible to examine the local immune response within the lung, the most commonly affected organ in sarcoidosis. In this study three different indices of cell mediated immunity (lymphocyte transformation, interleukin-2 production, and interleukin-1 production) have been examined by comparison of cells recovered by lavage with those collected from peripheral blood. It was found that in vitro anergy was confined to peripheral blood cells, where all three markers of the immune response used in this study was impaired in the 12 patients with sarcoidosis group when compared with results in the 12 controls, with the most depressed responses seen in those patients classified as having active disease (lymphocyte proliferation 45% (SD 17%); interleukin-2 production 44% (13%), and interleukin-1 production 31% (10%) of control levels). By contrast, T lymphocytes recovered from the lungs of patients with sarcoidosis showed a greater response than did those from controls in terms of lymphocyte transformation and interleukin-2 production; these differences were greatest in those with active disease (lymphocyte proliferation 209% (27%) and interleukin-2 production 202% (19%) of control levels). Interleukin-1 production by cells of the monocyte lineage recovered from the lung gave similar results to those of the control and sarcoid groups. It is concluded that the anergy seen in the peripheral blood compartment possibly reflects redistribution of T lymphocytes rather than a generalised immune deficiency.
Current standards and new concepts in MRI and PET response assessment of antiangiogenic therapies in high-grade glioma patients
Authors: M. Hutterer, E. Hattingen, C. Palm, M. A. Proescholdt, P. Hau
Journal: Neuro-Oncology (2014)

Despite multimodal treatment, the prognosis of high-grade gliomas is grim. As tumor growth is critically dependent on new blood vessel formation, antiangiogenic treatment approaches offer an innovative treatment strategy. Bevacizumab, a humanized monoclonal antibody, has been in the spotlight of antiangiogenic approaches for several years. Currently, MRI including contrast-enhanced T1-weighted and T2/fluid-attenuated inversion recovery (FLAIR) images is routinely used to evaluate antiangiogenic treatment response (Response Assessment in Neuro-Oncology criteria). However, by restoring the blood-brain barrier, bevacizumab may reduce T1 contrast enhancement and T2/FLAIR hyperintensity, thereby obscuring the imaging-based detection of progression. The aim of this review is to highlight the recent role of imaging biomarkers from MR and PET imaging on measurement of disease progression and treatment effectiveness in antiangiogenic therapies. Based on the reviewed studies, multimodal imaging combining standard MRI with new physiological MRI techniques and metabolic PET imaging, in particular amino acid tracers, may have the ability to detect antiangiogenic drug susceptibility or resistance prior to morphological changes. As advances occur in the development of therapies that target specific biochemical or molecular pathways and alter tumor physiology in potentially predictable ways, the validation of physiological and metabolic imaging biomarkers will become increasingly important in the near future.
Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer
Authors: Lilian E. van Vlerken, Zhenfeng Duan, Michael V. Seiden, Mansoor M. Amiji
Journal: Cancer Research (2007)

Abstract Although multidrug resistance (MDR) is known to develop through a variety of molecular mechanisms within the tumor cell, many tend to converge toward the alteration of apoptotic signaling. The enzyme glucosylceramide synthase (GCS), responsible for bioactivation of the proapoptotic mediator ceramide to a nonfunctional moiety glucosylceramide, is overexpressed in many MDR tumor types and has been implicated in cell survival in the presence of chemotherapy. The purpose of this study was to investigate the therapeutic strategy of coadministering ceramide with paclitaxel, a commonly used chemotherapeutic agent, in an attempt to restore apoptotic signaling and overcome MDR in the human ovarian cancer cell line SKOV3. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were used to encapsulate and deliver the therapeutic agents for enhanced efficacy. Results show that indeed the cotherapy eradicates the complete population of MDR cancer cells when they are treated at their IC50 dose of paclitaxel. More interestingly, when the cotherapy was combined with the properties of nanoparticle drug delivery, the MDR cells can be resensitized to a dose of paclitaxel near the IC50 of non-MDR (drug sensitive) cells, indicating a 100-fold increase in chemosensitization via this approach. Molecular analysis of activity verified the hypothesis that the efficacy of this therapeutic approach is indeed due to a restoration in apoptotic signaling, although the beneficial properties of PEO-PCL nanoparticle delivery seemed to enhance the therapeutic success even further, showing the promising potential for the clinical use of this therapeutic strategy to overcome MDR. [Cancer Res 2007;67(10):4843–50]
Association Between Surgical Indications, Operative Risk, and Clinical Outcome in Infective Endocarditis
Authors: Vivian H. Chu, Lawrence P. Park, Eugene Athan, Francois Delahaye, Tomas Freiberger, Cristiane Lamas, Jose M. Miro, Daniel W. Mudrick, Jacob Strahilevitz, Christophe Tribouilloy, Emanuele Durante-Mangoni, Juan M. Pericas, Nuria Fernández-Hidalgo, Francisco Nacinovich, Hussien Rizk, Vladimir Krajinovic, Efthymia Giannitsioti, John P. Hurley, Margaret M. Hannan, Andrew Wang
Journal: Circulation (2014)

Use of surgery for the treatment of infective endocarditis (IE) as related to surgical indications and operative risk for mortality has not been well defined.The International Collaboration on Endocarditis-PLUS (ICE-PLUS) is a prospective cohort of consecutively enrolled patients with definite IE from 29 centers in 16 countries. We included patients from ICE-PLUS with definite left-sided, non-cardiac device-related IE who were enrolled between September 1, 2008, and December 31, 2012. A total of 1296 patients with left-sided IE were included. Surgical treatment was performed in 57% of the overall cohort and in 76% of patients with a surgical indication. Reasons for nonsurgical treatment included poor prognosis (33.7%), hemodynamic instability (19.8%), death before surgery (23.3%), stroke (22.7%), and sepsis (21%). Among patients with a surgical indication, surgical treatment was independently associated with the presence of severe aortic regurgitation, abscess, embolization before surgical treatment, and transfer from an outside hospital. Variables associated with nonsurgical treatment were a history of moderate/severe liver disease, stroke before surgical decision, and Staphyloccus aureus etiology. The integration of surgical indication, Society of Thoracic Surgeons IE score, and use of surgery was associated with 6-month survival in IE.Surgical decision making in IE is largely consistent with established guidelines, although nearly one quarter of patients with surgical indications do not undergo surgery. Operative risk assessment by Society of Thoracic Surgeons IE score provides prognostic information for survival beyond the operative period. S aureus IE was significantly associated with nonsurgical management.
Histone Deacetylase Inhibitors Induce Premature Sister Chromatid Separation and Override the Mitotic Spindle Assembly Checkpoint
Authors: Laura Magnaghi-Jaulin, Grégory Eot-Houllier, Géraldine Fulcrand, Christian Jaulin
Journal: Cancer Research (2007)

Abstract Histone deacetylase inhibitors (HDACI) are powerful antiproliferative drugs, and are currently undergoing clinical trials as antitumor agents. It would be valuable for both cancer therapy and our knowledge of basic cellular processes to understand the mechanisms by which HDACIs block cell proliferation. Most current models postulate that HDACIs allow the reexpression of tumor suppressor genes silenced in cancer cells. However, other mechanisms, distinct from transcription regulation, may participate in HDACI antiproliferative properties. We report that HDACI treatment induces premature sister chromatid separation in cells in which the mitotic spindle assembly checkpoint (SAC) has already been activated. This effect was transcription-independent. In addition, HDACI-treated mitotic cells displayed SAC inactivation characteristics, including anaphase-promoting complex/cyclosome target degradation, cyclin-dependent kinase 1 inactivation, histone H3 dephosphorylation, and loss of the SAC component MAD2 from the kinetochore. Thus, HDAC inhibition renders the SAC ineffective. Our findings help elucidate the molecular mechanisms of proliferative cell death induced by HDACI treatment and may allow new HDACI-based preclinical and clinical trial protocols to be redesigned so as to target mitosis. [Cancer Res 2007;67(13):6360–7]
Public Reporting and Pay for Performance in Hospital Quality Improvement
Authors: Peter K. Lindenauer, Denise Remus, Sheila Roman, Michael B. Rothberg, Evan M. Benjamin, Allen Ma, Dale W. Bratzler
Journal: New England Journal of Medicine (2007)

Public reporting and pay for performance are intended to accelerate improvements in hospital care, yet little is known about the benefits of these methods of providing incentives for improving care.We measured changes in adherence to 10 individual and 4 composite measures of quality over a period of 2 years at 613 hospitals that voluntarily reported information about the quality of care through a national public-reporting initiative, including 207 facilities that simultaneously participated in a pay-for-performance demonstration project funded by the Centers for Medicare and Medicaid Services; we then compared the pay-for-performance hospitals with the 406 hospitals with public reporting only (control hospitals). We used multivariable modeling to estimate the improvement attributable to financial incentives after adjusting for baseline performance and other hospital characteristics.As compared with the control group, pay-for-performance hospitals showed greater improvement in all composite measures of quality, including measures of care for heart failure, acute myocardial infarction, and pneumonia and a composite of 10 measures. Baseline performance was inversely associated with improvement; in pay-for-performance hospitals, the improvement in the composite of all 10 measures was 16.1% for hospitals in the lowest quintile of baseline performance and 1.9% for those in the highest quintile (P<0.001). After adjustments were made for differences in baseline performance and other hospital characteristics, pay for performance was associated with improvements ranging from 2.6 to 4.1% over the 2-year period.Hospitals engaged in both public reporting and pay for performance achieved modestly greater improvements in quality than did hospitals engaged only in public reporting. Additional research is required to determine whether different incentives would stimulate more improvement and whether the benefits of these programs outweigh their costs.
Prediction of Mortality After Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction
Authors: Amir Halkin, Mandeep Singh, Eugenia Nikolsky, Cindy L. Grines, James E. Tcheng, Eulogio Garcia, David A. Cox, Mark Turco, Thomas D. Stuckey, Yingo Na, Alexandra J. Lansky, Bernard J. Gersh, William W. O’Neill, Roxana Mehran, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2005)
Lentiviral and targeted cellular barcoding reveals ongoing clonal dynamics of cell lines in vitro and in vivo
Authors: Shaina N Porter, Lee C Baker, David Mittelman, Matthew H Porteus
Journal: Genome biology (2014)

Cell lines are often regarded as clonal, even though this simplifies what is known about mutagenesis, transformation and other processes that destabilize them over time. Monitoring these clonal dynamics is important for multiple areas of biomedical research, including stem cell and cancer biology. Tracking the contributions of individual cells to large populations, however, has been constrained by limitations in sensitivity and complexity. We utilize cellular barcoding methods to simultaneously track the clonal contributions of tens of thousands of cells. We demonstrate that even with optimal culturing conditions, common cell lines including HeLa, K562 and HEK-293 T exhibit ongoing clonal dynamics. Starting a population with a single clone diminishes but does not eradicate this phenomenon. Next, we compare lentiviral and zinc-finger nuclease barcode insertion approaches, finding that the zinc-finger nuclease protocol surprisingly results in reduced clonal diversity. We also document the expected reduction in clonal complexity when cells are challenged with genotoxic stress. Finally, we demonstrate that xenografts maintain clonal diversity to a greater extent than in vitro culturing of the human non-small-cell lung cancer cell line HCC827. We demonstrate the feasibility of tracking and quantifying the clonal dynamics of entire cell populations within multiple cultured cell lines. Our results suggest that cell heterogeneity should be considered in the design and interpretation of in vitro culture experiments. Aside from clonal cell lines, we propose that cellular barcoding could prove valuable in modeling the clonal behavior of heterogeneous cell populations over time, including tumor populations treated with chemotherapeutic agents.