tbuckley/cabot-search huggingface dataset:
The Fallacy of Single-Agent Chemotherapy for Cancer
Authors: Henry S. Friedman, Jill Maxwell
Journal: Journal of Clinical Oncology (2007)

TO THE EDITOR: We have read with interest the editorial by Drs Stupp and Hegi entitled, “Methylguanine Methyltransferase Testing in Glioblastoma: When and How.” We would like to comment on the recommendation for separate trials for patients with unmethylated MGMT, which states that temozolomide should be replaced or other drugs added. We believe the available data that we have generated, make it clear that tumors with unmethylated MGMT promoters still have a large fraction of cells that do not stain positive for MGMT immunohistochemically and thus are potentially sensitive to temozolomide. Accordingly, rather than remove temozolomide from these patients’ treatment, it would appear far more rational to add other agents whose activities are not perturbed by MGMT. In addition, we advise against single-agent temozolomide even in patients whose tumors have methylation of the MGMT promoter based on similar concerns of heterogeneity and differential sensitivity. We believe this should be called the Brooklyn Bridge hypothesis (ie, if you believe single-agent chemotherapy will cure glioblastoma multiforme, then you are also a prime candidate to be sold this wonderful bridge in Brooklyn).
Controversies in Cancer Stem Cells: Targeting Embryonic Signaling Pathways
Authors: Naoko Takebe, S. Percy Ivy
Journal: Clinical Cancer Research (2010)

Selectively targeting cancer stem cells (CSC) or tumor-initiating cells (TIC; from this point onward referred to as CSCs) with novel agents is a rapidly emerging field of oncology. Our knowledge of CSCs and their niche microenvironments remains a nascent field. CSC's critical dependence upon self-renewal makes these regulatory signaling pathways ripe for the development of experimental therapeutic agents. Investigational agents targeting the Notch, Hedgehog, and Wnt pathways are currently in late preclinical development stages, with some early phase 1-2 testing in human subjects. This series of articles will provide an overview and summary of the current state of knowledge of CSCs, their interactive microenvironment, and how they may serve as important targets for antitumor therapies. We also examine the scope and stage of development of early experimental agents that specifically target these highly conserved embryonic signaling pathways.
Acute induction of human IL-8 production by intestinal epithelium triggers neutrophil infiltration without mucosal injury
Authors: T Kucharzik
Journal: Gut (2005)

<b>Aim:</b> Neutrophil migration in the intestine depends on chemotaxis of neutrophils to CXC chemokines produced by epithelial cells. The goal of this project was to determine if acute induction of a CXC chemokine gradient originating from intestinal epithelial cells is sufficient to induce neutrophil influx into intact intestinal tissue. <b>Methods and results:</b> The authors developed a double transgenic mouse model with doxycycline induced human IL-8 expression restricted to intestinal epithelial cells. Doxycycline treatment of double transgenic mice for three days resulted in a 50-fold increase in the caecal IL-8 concentration and influx of neutrophils into the lamina propria. Although neutrophils entered the paracellular space between epithelial cells, complete transepithelial migration was not observed. Doxycycline treatment also increased the water content of the caecal and colonic stool, indicating dysfunctional water transport. However, the transmural electrical resistance was not decreased. Neutrophils recruited to the intestinal epithelium did not show evidence of degranulation and the epithelium remained intact as judged by histology. <b>Conclusions:</b> This conditional transgenic model of chemokine expression provides evidence that acute induction of IL-8 in the intestinal epithelium is sufficient to trigger neutrophil recruitment to the lamina propria, but additional activation signals are needed for full activation and degranulation of neutrophils, mucosal injury, and complete transepithelial migration.
Parstatin: a cryptic peptide involved in cardioprotection after ischaemia and reperfusion injury
Authors: J. L. Strande, M. E. Widlansky, N. E. Tsopanoglou, J. Su, J. Wang, A. Hsu, K. V. Routhu, J. E. Baker
Journal: Cardiovascular Research (2009)

Aims Thrombin activates protease-activated receptor 1 by proteolytic cleavage of the N-terminus.Although much research has focused on the activated receptor, little is known about the 41-amino acid N-terminal peptide (parstatin).We hypothesized that parstatin would protect the heart against ischaemia-reperfusion injury. Methods and resultsWe assessed the protective role of parstatin in an in vivo and in vitro rat model of myocardial ischaemia-reperfusion injury.Parstatin treatment before, during, and after ischaemia decreased infarct size by 26%, 23%, and 18%, respectively, in an in vivo model of ischaemia-reperfusion injury.Parstatin treatment immediately before ischaemia decreased infarct size by 65% and increased recovery in ventricular function by 23% in an in vitro model.We then assessed whether parstatin induced cardioprotection by activation of a Gi-protein-dependent pathway.Gi-protein inactivation by pertussis toxin completely abolished the cardioprotective effects.The cardioprotective effects were also abolished by inhibition of nitric oxide synthase (NOS), extracellular signal-regulated kinases 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), and K ATP channels in vitro.Furthermore, parstatin increased coronary flow and decreased perfusion pressure in the isolated heart.The vasodilatory properties of parstatin were confirmed in rat coronary arterioles.Conclusion A single treatment of parstatin administered prior to ischaemia confers immediate cardioprotection by recruiting the Gi-protein activation pathway including p38 MAPK, ERK1/2, NOS, and K ATP channels.Parstatin exerts effects on both the cardiomyocytes and the coronary circulation to induce cardioprotection.This suggests a potential therapeutic role of parstatin in the treatment of cardiac injury resulting from ischaemia and reperfusion.
Social Cognition and Neurocognition: Effects of Risperidone, Olanzapine, and Haloperidol
Authors: Mark J. Sergi, Michael F. Green, Clifford Widmark, Christopher Reist, Stephen Erhart, David L. Braff, Kimmy S. Kee, Stephen R. Marder, Jim Mintz
Journal: American Journal of Psychiatry (2007)

Objective: This study examined the short-term effects of first- and second-generation antipsychotic medications on social cognition and basic cognition. Method: One hundred patients with schizophrenia or schizoaffective disorder participated in an 8 week, double-blind study of risperidone, olanzapine, and haloperidol. Participants were administered multiple measures of social cognition, basic cognition, and clinical symptoms at baseline, the end of week 4, and the end of week 8. Seventy-three patients completed the baseline assessment and at least one other assessment. Data were analyzed with mixed-effects analyses of covariance. For data reduction, the social cognitive measures were clustered into a summary score, and the cognitive measures were clustered into two summary scores: general cognitive ability and processing speed. (The effects on thinking of risperidone and olanzapine can be found at NCT00108368, www.clinicaltrials.gov.) Results: There were no treatment-related differences on any of the three summary scores. Social cognition did not show within-group changes over time either by itself or after control for the cognitive clusters. One cognitive score (general cognitive ability) increased during the study period for all three medication groups. Conclusions: The present study included a rather thorough assessment of social cognition and did not find any evidence of between-group or within-group effects of antipsychotic medication on social cognition.
Tissue inhibitor of metalloproteinases-2 gene polymorphisms in chronic obstructive pulmonary disease
Authors: K. Hirano, T. Sakamoto, Y. Uchida, Y. Morishima, K. Masuyama, Y. Ishii, A. Nomura, M. Ohtsuka, K. Sekizawa
Journal: European Respiratory Journal (2001)

Proteinase/antiproteinase imbalance is the most widely accepted theory for development of chronic obstructive pulmonary disease (COPD). Mutations of tissue inhibitor of metalloproteinases-;2 (TIMP-;2) that downregulate its activity may increase the activities of matrix metalloproteinases and result in the degradation of the lung matrix. Polymorphisms of the TIMP-;2 gene were investigated in 88 COPD patients and 40 control subjects. The variations were examined by single-strand conformational polymorphism analysis followed by sequencing. Two polymorphisms were identified, +853 G/A and −418 G/C nucleotide substitutions. There was a significant deviation in the genotypic frequencies at +853 and the allele frequencies for G were significantly higher in the COPD patient group than in the control group. For locus −418, the allele frequencies for C in the COPD patient group also tended to be higher than those in the control group. The +853 G/A nucleotide substitution was a silent variant. The −418 G/C substitution was located in the consensus sequence for the Sp1 binding site. These polymorphisms may be associated with the development of chronic obstructive pulmonary disease, decreasing the transcription and stability of the messenger ribonucleic acid, and available as genetic markers of susceptibility to the disease.
Implantable Cardioverter Defibrillator Therapy
Authors: Arthur J. Moss
Journal: Circulation (2000)

t times, our clinical intuition may lead us down the wrong path, but the scientific method helps direct us back to the proper course.In 1970, Mirowski et al 1 published their first experience with the standby automatic defibrillator in animals, but their innovative approach to prevent sudden cardiac death was not initially accepted by the cardiac community.Concerns about the practicality of the implanted defibrillator to save lives stimulated Mirowski and colleagues to perform additional investigations; this culminated in their 1980 publication documenting life-saving internal defibrillation with an implantable device in 3 patients. 2The era of the clinical use of the implantable cardioverter defibrillator (ICD) therapy began just 20 years ago, and progress in the field since that time has been astounding.
Exacerbated vein graft arteriosclerosis in protein kinase Cδ–null mice
Authors: Michael Leitges, Manuel Mayr, Ursula Braun, Ursula Mayr, Chaohong Li, Gerald Pfister, Nassim Ghaffari-Tabrizi, Gottfried Baier, Yanhua Hu, Qingbo Xu
Journal: Journal of Clinical Investigation (2001)

Smooth muscle cell (SMC) accumulation is a key event in the development of atherosclerosis, including vein bypass graft arteriosclerosis. Because members of the protein kinase C (PKC) family signal cells to undergo proliferation, differentiation, or apoptosis, we generated PKCδ knockout mice and performed vein bypass grafts on these animals. PKCδ–/– mice developed normally and were fertile. Vein segments from PKCδ–/– mice isografted to carotid arteries of recipient mice of either genotype led to a more severe arteriosclerosis than was seen with PKCδ+/+ vein grafts. Arteriosclerotic lesions in PKCδ–/– mice showed a significantly higher number of SMCs than were found in wild-type animals; this was correlated with decreased SMC death in lesions of PKCδ–/– mice. SMCs derived from PKCδ–/– aortae were resistant to cell death induced by any of several stimuli, but they were similar to wild-type SMCs with respect to mitogen-stimulated cell proliferation in vitro. Furthermore, pro-apoptotic treatments led to diminished caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and cytochrome c release in PKCδ–/– relative to wild-type SMCs, suggesting that their apoptotic resistance involves the loss of free radical generation and mitochondrial dysfunction in response to stress stimuli. Our data indicate that PKCδ maintains SMC homeostasis and that its function in the vessel wall per se is crucial in the development of vein graft arteriosclerosis.
Poly(ADP-ribose) polymerase activation in the reperfused myocardium
Authors: Gábor Szabó, Lucas Liaudet, Siegfried Hagl, Csaba Szabó
Journal: Cardiovascular Research (2004)

The activation of poly(ADP-ribose) polymerase (PARP) is now considered a final common effector in various types of tissue injury including systemic inflammation, circulatory shock and ischemia/reperfusion. Free radical and oxidant production and related cytotoxicity during ischemia/reperfusion leads to DNA strand breakage which activates the nuclear enzyme PARP and initiates an energy-consuming, inefficient cellular metabolic cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. During the last 5 years, a growing number of experimental studies demonstrated the beneficial effects of PARP inhibition in cell cultures through rodent models and more recently in pre-clinical large animal models of regional and global ischemia/reperfusion injury. The objective of the current review is to provide an overview of the experimental evidence implicating PARP as a pathophysiological modulator of myocardial injury in vitro and in vivo.
IL-18 Attenuates Experimental Choroidal Neovascularization as a Potential Therapy for Wet Age-Related Macular Degeneration
Authors: Sarah L. Doyle, Ema Ozaki, Kiva Brennan, Marian M. Humphries, Kelly Mulfaul, James Keaney, Paul F. Kenna, Arvydas Maminishkis, Anna-Sophia Kiang, Sean P. Saunders, Emily Hams, Ed C. Lavelle, Clair Gardiner, Padraic G. Fallon, Peter Adamson, Peter Humphries, Matthew Campbell
Journal: Science Translational Medicine (2014)

IL-18 prevents choroidal neovascularization, the hallmark pathology of wet AMD, and is not toxic to the retinal pigment epithelium.
Modern cardiovascular physiology
Authors: David A. Brodie
Journal: British Journal of Sports Medicine (1988)

This is a reworked edition of Carl Honig's original text with many improvements particularly in terms of clarity.The themes of 'reserve of function' and the 'systems concept' run throughout the book which is divided into five parts.quote from the Preface which states that; 'The first two deal with the biophysical essentials: cardiac mechanics, electrophysiology, and hemodynamics.The third part is concerned with exchanges between blood and tissue, including new concepts in °2 transport.The fourth part describes selected regional circulations.This idiosyncratic material has been simplified by use of a common approach.The final part develops the regulation of pressure, flow, and volume and the integration of cardiovascular controls with voluntary behaviour."Each chapter contains clinical applications which highlight the relevance of the text and concludes with a brief but relevant list of references.The appendices include a number of problems and suggested approaches for solving them which is excellent revisionary material.The figures within the text utilise a full range of techniques including electron micrographs, flow diagrams and models.The book illustrates the importance of the basic physical sciences to full understanding.It will be a valued text for all medical or health science undergraduates and useful in many post-graduate courses.
Asymmetric Dimethylarginine Is Increased in Chronic Thromboembolic Pulmonary Hypertension
Authors: Nika Skoro-Sajer, Friedrich Mittermayer, Adelheid Panzenboeck, Diana Bonderman, Roela Sadushi, Robert Hitsch, Johannes Jakowitsch, Walter Klepetko, Meinhard P. Kneussl, Michael Wolzt, Irene M. Lang
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Asymmetric dimethylarginine (ADMA), a potent endogenous nitric oxide synthase (NOS) inhibitor, is increased in idiopathic pulmonary arterial hypertension and associated with unfavorable outcome.Chronic thromboembolic pulmonary hypertension (CTEPH), although principally amenable to surgical removal of major pulmonary arterial obstructions by pulmonary endarterectomy, may show a small-vessel pulmonary arteriopathy similar to idiopathic pulmonary arterial hypertension. We hypothesized that ADMA plasma levels are increased in patients with CTEPH.We measured ADMA by high-performance liquid chromatography at the time of diagnosis in 135 patients with CTEPH. Inoperability in 66 patients was based on an imbalance between severity of pulmonary hypertension and morphologic lesions.ADMA plasma levels were significantly elevated in patients, compared with 40 matched control subjects (0.62 [0.51-0.73] vs. 0.51 [0.45-0.6] micromol/L, P = 0.0002). At baseline, ADMA plasma concentrations correlated with mixed venous saturation (r = -0.25, P = 0.005), right atrial pressure (r = 0.35, P < 0.0001), and cardiac index (r = -0.21, P = 0.01). Patients who underwent surgery demonstrated lower ADMA levels at baseline than inoperable patients (0.60 [0.5-0.68] vs. 0.63 [0.53-0.85] micromol/L, P = 0.02), with a further decrease 12 +/- 1 months after pulmonary endarterectomy (P = 0.02). Endothelial NOS expression in endothelial cells was low in patients with elevated ADMA plasma levels. Survival of patients with ADMA plasma levels >/= 0.64 micromol/L was worse than in patients with ADMA plasma levels < 0.64 micromol/L.ADMA plasma levels correlate with the severity of pulmonary vascular disease and predict outcome in patients with CTEPH. Measurement of ADMA plasma levels may be useful for estimating the degree of small-vessel arteriopathy in CTEPH.
C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease
Authors: S F P Man
Journal: Thorax (2006)

<b>Background:</b> Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. <b>Methods:</b> Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. <b>Results:</b> CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p&lt;0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for ⩾5 year mortality. <b>Conclusions:</b> CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.
Acute and Prolonged Effects of Sildenafil on Brachial Artery Flow-Mediated Dilatation in Type 2 Diabetes
Authors: Cyrus Desouza, Akhil Parulkar, David Lumpkin, Donald Akers, Vivian A. Fonseca
Journal: Diabetes Care (2002)

OBJECTIVE—Flow-mediated dilatation (FMD), induced by occlusion of the brachial artery, is an index of nitric oxide-dependent endothelial function that is impaired in patients with type 2 diabetes. Sildenafil (Viagra) is an inhibitor of phosphodiesterase 5 (PDE-5), which is used for management of erectile dysfunction in a broad range of patients, including those with type 2 diabetes. Its effects on endothelial function in these patients have not been previously assessed. RESEARCH DESIGN AND METHODS—We assessed the acute and prolonged effects of a low dose of sildenafil (25 mg) on FMD in patients with type 2 diabetes. We performed a double-blind, placebo-controlled cross-over trial in 16 patients (14 of whom completed the study) with type 2 diabetes who had erectile dysfunction without overt clinical heart disease. RESULTS—In these patients, the mean ± SD brachial artery diameter (BAD) measured by ultrasound was 4.33 ± 0.6 mm. After inducing FMD, the BAD increased 8% to 4.66 ± 0.6 mm (P = 0.2). One hour after oral administration of sildenafil 25 mg, FMD increased the BAD significantly by 15% to 4.99 ± 0.5 mm (P ≤ 0.01), whereas it did not change with placebo (4.6 ± 0.6 mm, P = 0.1). After treatment with sildenafil 25 mg daily for 2 weeks and testing 24 h after the last dose, the mean FMD was 14% (P = 0.01). In contrast, the mean FMD with placebo was 9% (P = 0.45). CONCLUSIONS—We conclude that acute and prolonged sildenafil treatment has a favorable effect on brachial artery flow-mediated dilatation that persists for at least 24 h after the last dose. Further investigation is needed to determine whether this prolonged effect has clinical implications in patients with type 2 diabetes.
Usefulness of bronchoalveolar lavage in the diagnosis of desquamative interstitial pneumonia
Authors: Thomas Wessendorf, Francesco Bonella, Dirk Theegarten, Ulrich Costabel
Journal: European Respiratory Journal (2014)

Introduction:  Desquamative interstitial pneumonia (DIP) is a rare, usually smoking associated interstitial pneumonia. It is known that eosinophils are present in the bronchoalveolar lavage (BAL) of DIP in a variable percentage. Aim of this study was to verify how BAL differential cell count may contribute to the diagnosis of DIP.   Patients and Methods:  29 subjects (18 men, 11 women, 52 ± 14 years) with a diagnosis of DIP were studied retrospectively. Diagnosis of DIP was histologically confirmed by surgical lung biopsy in 16 patients and by transbronchial biopsy in 1 patient. In 12 patients without histological confirmation the diagnosis was made on the basis of the clinical and radiological data and the typical clinical course (poor response to corticosteroids and long-term progression) .   Results:  BAL eosinophilia was seen in all subjects with different severity (15 ± 19%, range 1.0 – 62.3, mean ± SD), leading initially to the incorrect diagnosis of eosinophilic pneumonia in 5 pts. The percentage of lymphocytes was normal in all subjects: 5 ± 4% (range 0 -15.0). The total cell number was increased (18 ± 13 Mio/µl). BAL of patients with histologically proven DIP was not different from the others.   Conclusion:  BAL cellularity in DIP is increased as well as the number of eosinophils. A very high percentage of eosinophils may lead to the misdiagnosis of eosinophilic pneumonia. DIP should be included in the differential diagnosis of BAL eosinophilia. On the other hand, an increase in BAL lymphocytes as well as a normal eosinophilic count may exclude DIP from the list of differential diagnoses.
Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer
Authors: Elisabeth H. Slager, M. Willy Honders, Edith D. van der Meijden, Simone A. P. van Luxemburg-Heijs, Freke M. Kloosterboer, Michel G. D. Kester, Inge Jedema, W. A. Erik Marijt, M. Ron Schaafsma, Roel Willemze, J. H. Frederik Falkenburg
Journal: Blood (2006)
Mitochondrial DNA Mutation in Serous Ovarian Cancer: Implications for Mitochondria-Coded Genes in Chemoresistance
Authors: Flora Guerra, Anna Myriam Perrone, Ivana Kurelac, Donatella Santini, Claudio Ceccarelli, Monica Cricca, Claudio Zamagni, Pierandrea De Iaco, Giuseppe Gasparre
Journal: Journal of Clinical Oncology (2012)