tbuckley/cabot-search huggingface dataset:
Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic
Authors: Mark S. Cragg, Elisa S. Jansen, Michele Cook, Claire Harris, Andreas Strasser, Clare L. Scott
Journal: Journal of Clinical Investigation (2008)

B-RAF is frequently mutated in solid tumors, resulting in activation of the MEK/ERK signaling pathway and ultimately tumor cell growth and survival. MEK inhibition in these cells results in cell cycle arrest and cytostasis. Here, we have shown that MEK inhibition also triggers limited apoptosis of human tumor cell lines with B-RAF mutations and that this effect was dependent on upregulation and dephosphorylation of the proapoptotic, Bcl-2 homology 3-only (BH3-only) Bcl-2 family member Bim. However, upregulation of Bim was insufficient for extensive apoptosis and was countered by overexpression of Bcl-2. To overcome apoptotic resistance, we treated the B-RAF mutant cells both with MEK inhibitors and with the BH3 mimetic ABT-737, resulting in profound synergism and extensive tumor cell death. This treatment was successful because of both efficient antagonism of the prosurvival Bcl-2 family member Mcl-1 by Bim and inhibition of Bcl-2 and Bcl-x(L) by ABT-737. Critically, addition of ABT-737 converted the predominantly cytostatic effect of MEK inhibition to a cytotoxic effect, causing long-term tumor regression in mice xenografted with human tumor cell lines. Thus, the therapeutic efficacy of MEK inhibition requires concurrent unleashing of apoptosis by a BH3 mimetic and represents a potent combination treatment for tumors harboring B-RAF mutations.
Fasting motor activity occurs during a day of normal meals in healthy subjects.
Authors: D G Thompson, L Archer, W J Green, D L Wingate
Journal: Gut (1981)

Using a radiotelemetric technique of pressure recording which did not interfere with normal feeding, jejunal motor activity was recorded in seven healthy human subjects, who were given three hospital meals during the course of a day, and allowed ad libitum supplementary snacks. Fasting motor activity was detected during the day in five subjects, and, although its occurrence was very variable, tended to occur shortly before the next meal.
Survival analysis in patients with newly diagnosed glioblastoma using pre- and postradiotherapy MR spectroscopic imaging†
Authors: Yan Li, Janine M. Lupo, Rupa Parvataneni, Kathleen R. Lamborn, Soonmee Cha, Susan M. Chang, Sarah J. Nelson
Journal: Neuro-Oncology (2013)

The objective of this study was to examine the predictive value of parameters of 3D 1H magnetic resonance spectroscopic imaging (MRSI) prior to treatment with radiation/chemotherapy (baseline) and at a postradiation 2-month follow-up (F2mo) in relationship to 6-month progression-free survival (PFS6) and overall survival (OS). Sixty-four patients with newly diagnosed glioblastoma multiforme (GBM) being treated with radiation and concurrent chemotherapy were involved in this study. Evaluated were metabolite indices and metabolite ratios. Logistic linear regression and Cox proportional hazards models were utilized to evaluate PFS6 and OS, respectively. These analyses were adjusted by age and MR scanner field strength (1.5 T or 3 T). Stepwise regression was performed to determine a subset of the most relevant variables. Associated with shorter PFS6 were a decrease in the ratio of N-acetyl aspartate to choline-containing compounds (NAA/Cho) in the region with a Cho-to-NAA index (CNI) >3 at baseline and an increase of the CNI within elevated CNI regions (>2) at F2mo. Patients with higher normalized lipid and lactate at either time point had significantly worse OS. Patients who had larger volumes with abnormal CNI at F2mo had worse PFS6 and OS. Our study found more 3D MRSI parameters that predicted PFS6 and OS for patients with GBM than did anatomic, diffusion, or perfusion imaging, which were previously evaluated in the same population of patients.
Are metallic stents really safe? A long-term analysis in lung transplant recipients
Authors: J. Gottlieb, T. Fuehner, M. Dierich, O. Wiesner, A. R. Simon, T. Welte
Journal: European Respiratory Journal (2009)

Airway complications affect 20% of all lung transplant recipients. Self-expandable metallic stents (SEMS) are one treatment option but their use in benign airway disorders is controversial. We studies the long-term safety of SEMS in lung transplant recipients. Between January 1998 and February 2008, all lung transplant recipients with SEMS were analysed retrospectively at a single centre. Complications were recorded until September 2008. In 65 (9.2%) out of 706 recipients, 111 (91% noncovered) bronchial SEMS were implanted a median (range) 133 (55-903) days after lung transplantation; follow-up was 777 (7-3.655) days. Clinical improvement was noted in 80% of recipients. The forced expiratory volume in 1 s increased by (mean+/-SD) 21+/-33%. Most frequent early complications were migration (3%) and mucus plugging (11%). No procedure-related deaths were noted. Re-stenosis occurred in 34 (52%) out of 65 recipients 85 (7-629) days after insertion. In multivariate analysis, stent insertion before post-operative day 90 was independently associated with an increased risk of re-stenosis (HR 3.29, 95% CI 1.50-7.18; p = 0.003). In 40% of recipients, new bacterial airway colonisation occurred after SEMS insertion. In SEMS patients, 5-yr survival was significantly lower than in the total cohort (60% versus 76%; p = 0.02). Late complications in lung transplant recipients treated with SEMS are frequent. The major problems are re-stenosis and airway colonisation.
Mobile teledermatology in Ghana: Sending and answering consults via mobile platform
Authors: Achiamah Osei-tutu, Ting Shih, Alyx Rosen, Nathan Amanquah, Mridul Chowdhury, Rajiv I. Nijhawan, Daniel Siegel, Carrie Kovarik
Journal: Journal of the American Academy of Dermatology (2013)
Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase II and Protein Kinase A Differentially Regulate Sarcoplasmic Reticulum Ca <sup>2+</sup> Leak in Human Cardiac Pathology
Authors: Thomas H. Fischer, Jonas Herting, Theodor Tirilomis, André Renner, Stefan Neef, Karl Toischer, David Ellenberger, Anna Förster, Jan D. Schmitto, Jan Gummert, Friedrich A. Schöndube, Gerd Hasenfuss, Lars S. Maier, Samuel Sossalla
Journal: Circulation (2013)

Sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptor type 2 (RyR2) dysfunction is of major pathophysiological relevance in human heart failure (HF); however, mechanisms underlying progressive RyR2 dysregulation from cardiac hypertrophy to HF are still controversial.We investigated healthy control myocardium (n=5) and myocardium from patients with compensated hypertrophy (n=25) and HF (n=32). In hypertrophy, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both phosphorylated RyR2 at levels that were not different from healthy myocardium. Accordingly, inhibitors of these kinases reduced the SR Ca(2+) leak. In HF, however, the SR Ca(2+) leak was nearly doubled compared with hypertrophy, which led to reduced systolic Ca(2+) transients, a depletion of SR Ca(2+) storage and elevated diastolic Ca(2+) levels. This was accompanied by a significantly increased CaMKII-dependent phosphorylation of RyR2. In contrast, PKA-dependent RyR2 phosphorylation was not increased in HF and was independent of previous β-blocker treatment. In HF, CaMKII inhibition but not inhibition of PKA yielded a reduction of the SR Ca(2+) leak. Moreover, PKA inhibition further reduced SR Ca(2+) load and systolic Ca(2+) transients.In human hypertrophy, both CaMKII and PKA functionally regulate RyR2 and may induce SR Ca(2+) leak. In the transition from hypertrophy to HF, the diastolic Ca(2+) leak increases and disturbed Ca(2+) cycling occurs. This is associated with an increase in CaMKII- but not PKA-dependent RyR2 phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic target for the treatment of arrhythmias and contractile dysfunction.
William Penny Brookes (1809–1895): forgotten Olympic Lord of the Rings: Figure 1
Authors: H Ashrafian
Journal: British Journal of Sports Medicine (2005)

The contribution of Dr William Penny Brookes (1809–1895) to the Olympic Games is scarcely reported in the medical literature. Presented here is a brief report of his life and work. Furthermore, the need to promote public health and fitness through the Olympics is re-emphasised.
<i>Haemophilus influenzae</i> from Patients with Chronic Obstructive Pulmonary Disease Exacerbation Induce More Inflammation than Colonizers
Authors: Cecilia L. Chin, Lori J. Manzel, Erin E. Lehman, Alicia L. Humlicek, Lei Shi, Timothy D. Starner, Gerene M. Denning, Timothy F. Murphy, Sanjay Sethi, Dwight C. Look
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Airway infection with Haemophilus influenzae causes airway inflammation, and isolation of new strains of this bacteria is associated with increased risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD).To determine whether strains of H. influenzae associated with exacerbations cause more inflammation than strains that colonize the airways of patients with COPD.Exacerbation strains of H. influenzae were isolated from patients during exacerbation of clinical symptoms with subsequent development of a homologous serum antibody response and were compared with colonization strains that were not associated with symptom worsening or an antibody response. Bacterial strains were compared using an in vivo mouse model of airway infection and in vitro cell culture model of bacterial adherence and defense gene and signaling pathway activation in primary human airway epithelial cells.H. influenzae associated with exacerbations caused more airway neutrophil recruitment compared with colonization strains in the mouse model of airway bacterial infection. Furthermore, exacerbation strains adhered to epithelial cells in significantly higher numbers and induced more interleukin-8 release after interaction with airway epithelial cells. This effect was likely mediated by increased activation of the nuclear factor-kappaB and p38 mitogen-activated protein kinase signaling pathways.The results indicate that H. influenzae strains isolated from patients during COPD exacerbations often induce more airway inflammation and likely have differences in virulence compared with colonizing strains. These findings support the concept that bacteria infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function.
Mitochondrial Oxidative Stress: Implications for Cell Death
Authors: Sten Orrenius, Vladimir Gogvadze, Boris Zhivotovsky
Journal: The Annual Review of Pharmacology and Toxicology (2006)

In addition to the established role of the mitochondria in energy metabolism, regulation of cell death has emerged as a second major function of these organelles. This seems to be intimately linked to their generation of reactive oxygen species (ROS), which have been implicated in mtDNA mutations, aging, and cell death. Mitochondrial regulation of apoptosis occurs by mechanisms, which have been conserved through evolution. Thus, many lethal agents target the mitochondria and cause release of cytochrome c and other pro-apoptotic proteins into the cytoplasm. Cytochrome c release is initiated by the dissociation of the hemoprotein from its binding to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and increases the level of soluble cytochrome c in the intermembrane space. Subsequent release of the hemoprotein occurs by pore formation mediated by pro-apoptotic Bcl-2 family proteins, or by Ca(2+) and ROS-triggered mitochondrial permeability transition, although the latter pathway might be more closely associated with necrosis. Taken together, these findings have placed the mitochondria in the focus of current cell death research.
Generalized Osteoporosis in Old Age
Authors: C. M. Kesson, N. Morris, A. McCutcheon
Journal: Annals of the Rheumatic Diseases (1947)

Infection with <i>Trypanosoma cruzi</i> results in the development of both type 1 and type 2 patterns of cytokine responses during acute and chronic stages of infection. To investigate the role of Th1 and Th2 subsets of CD4<sup>+</sup> T cells in determining the outcome of <i>T. cruzi</i> infection in mice, we have developed <i>T. cruzi</i> clones that express OVA and have used OVA-specific TCR-transgenic T cells to generate OVA-specific Th1 and Th2 cells. BALB/c mice receiving 10<sup>7</sup> OVA-specific Th1 cells and then challenged with OVA-expressing <i>T. cruzi</i> G-OVA.GPI showed significantly lower parasitemia and increased survival in comparison to mice that received no cells. In contrast, recipients of OVA-specific Th2 cells developed higher parasitemias, exhibited higher tissue parasitism and inflammation, and had higher mortality than recipients of Th1 cells after infection with <i>T. cruzi</i> G-OVA.GPI. Mice receiving a mixture of both Th1 and Th2 OVA-specific cells also were not protected from lethal challenge. The protective effect of the OVA-specific Th1 cells was OVA dependent as shown by the fact that transfer of OVA-specific Th1 or Th2 cells failed to alter the course of infection or disease in mice challenged with wild-type <i>T. cruzi</i>. Immunohistochemical analysis of OVA-specific Th1 and Th2 cells at 4, 15, and 30 days postinfection revealed the persistence and expansion of these cells in mice challenged with <i>T. cruzi</i> G-OVA.GPI but not in mice infected with wild-type <i>T. cruzi</i>. We conclude that transfer of Ag-specific Th1 cells but not Th2 cells protect mice from a lethal infection with <i>T. cruzi.</i>
Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes
Authors: Nitin Udpa, Roy Ronen, Dan Zhou, Junbin Liang, Tsering Stobdan, Otto Appenzeller, Ye Yin, Yuanping Du, Lixia Guo, Rui Cao, Yu Wang, Xin Jin, Chen Huang, Wenlong Jia, Dandan Cao, Guangwu Guo, Victoria E Claydon, Roger Hainsworth, Jorge L Gamboa, Mehila Zibenigus, Guta Zenebe, Jin Xue, Siqi Liu, Kelly A Frazer, Yingrui Li, Vineet Bafna, Gabriel G Haddad
Journal: Genome biology (2014)

Although it has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome, interpretation of the results was limited. We report here the results of the first whole genome resequencing-based analysis identifying genes that likely modulate high altitude adaptation in native Ethiopians residing at 3,500 m above sea level on Bale Plateau or Chennek field in Ethiopia. Using cross-population tests of selection, we identify regions with a significant loss of diversity, indicative of a selective sweep. We focus on a 208 kbp gene-rich region on chromosome 19, which is significant in both of the Ethiopian subpopulations sampled. This region contains eight protein-coding genes and spans 135 SNPs. To elucidate its potential role in hypoxia tolerance, we experimentally tested whether individual genes from the region affect hypoxia tolerance in Drosophila. Three genes significantly impact survival rates in low oxygen: cic, an ortholog of human CIC, Hsl, an ortholog of human LIPE, and Paf-AHα, an ortholog of human PAFAH1B3. Our study reveals evolutionarily conserved genes that modulate hypoxia tolerance. In addition, we show that many of our results would likely be unattainable using data from exome sequencing or microarray studies. This highlights the importance of whole genome sequencing for investigating adaptation by natural selection.
Release of Adenosine by the Normal Myocardium in Dogs and Its Relationship to the Regulation of Coronary Resistance
Authors: Rafael Rubio, Robert M. Berne
Journal: Circulation Research (1969)

The evidence supporting the hypothesis that adenosine is the mediator of metabolic regulation of coronary blood flow was obtained from experiments characterized by myocardial hypoxia. If adenosine serves the role of physiological regulator of coronary blood flow, it must also be released by the normal heart. Experiments designed to study this question were performed on 15 open-chest dogs in which adenosine was sought in perfusates of the epicardial surface of the well-oxygenated heart. The pericardial space was perfused with warm (37°C) Tyrode's or Krebs-Henseleit solutions (400 to 1200 ml over 1 to 3 hours), and the perfusates were analyzed for adenosine. With a normal myocardial oxygen supply, adenosine was present in the perfusates in a concentration of 3.1 ± 0.5 x 10&gt; -8 M. Partial asphyxia, induced by reducing pulmonary ventilation, significantly ( P ≤ 0.02) increased the adenosine concentration of the perfusates to 5.4 ± 0.8 x 10 -8 M. In four dogs the normal pericardial fluid was found to contain adenosine in a concentration of 10.9 ± 2.9 x 10 -7 M, which probably represents the basal extracellular adenosine concentration in the myocardium. The results indicate that the normal myocardial cells release adenosine continuously into the surrounding interstitial fluid, and it is suggested that the level of the interstitial fluid concentration of adenosine probably regulates coronary blood flow to maintain the oxygen balance of the myocardium.
The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation
Authors: Hyun Ho Park, Yu-Chih Lo, Su-Chang Lin, Liwei Wang, Jin Kuk Yang, Hao Wu
Journal: Annual Review of Immunology (2007)

The death domain (DD) superfamily comprising the death domain (DD) subfamily, the death effector domain (DED) subfamily, the caspase recruitment domain (CARD) subfamily, and the pyrin domain (PYD) subfamily is one of the largest domain superfamilies. By mediating homotypic interactions within each domain subfamily, these proteins play important roles in the assembly and activation of apoptotic and inflammatory complexes. In this chapter, we review the molecular complexes assembled by these proteins, the structural and biochemical features of these domains, and the molecular interactions mediated by them. By analyzing the potential molecular basis for the function of these domains, we hope to provide a comprehensive understanding of the function, structure, interaction, and evolution of this important family of domains.
Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer
Authors: N. Kemeny, M. Capanu, M. D'Angelica, W. Jarnagin, D. Haviland, R. Dematteo, Y. Fong
Journal: Annals of Oncology (2009)
Efficacy, safety, and cost of new anticancer drugs
Authors: S. Garattini
Journal: BMJ (2002)

Italian pharmacologists Silvio Garattini and Vittorio Bertele' note that new anticancer drugs reaching the European market in 1995-2000 offered few or no substantial advantages over existing preparations, yet cost several times—in one case 350 times—as much

Though only an imperfect indicator of progress in cancer control,1 age standardised mortality in the European Union, for both sexes combined, had been increasing up to 1988; since then it has decreased from 147 to 136 per 100 000 inhabitants.2 Prevention is probably one of the main reasons for this drop, particularly the decrease in tobacco smoking; another reason is the use of screening for early diagnosis of cancers of the cervix and breast and possibly also of the colon and rectum..

The greatest changes have been 4500 fewer deaths from childhood tumours and 4000 fewer from lymphomas (Hodgkin's disease) each year over the past four decades. Among solid tumours, advances have been made in treating breast cancer, in which tamoxifen increases 10 year survival by 6% for node negative and 11% for node positive tumours,3 and chemotherapy increases survival by 7% and 11%, respectively.4 For most other common solid tumours such as those of lung, oesophagus, stomach, or pancreas, only limited survival gains have been achieved. 256

On the whole, pharmacological treatments are credited with only a very small proportion of cures.7 However, some kind of pharmacological intervention is often considered as a last resort, particularly when cancer has already disseminated. We evaluated the progress made over the past few years in terms of new drugs approved for prescription in order to judge their likely impact on cancer mortality in the near …
Alteration of Topoisomerase II–Alpha Gene in Human Breast Cancer: Association With Responsiveness to Anthracycline-Based Chemotherapy
Authors: Michael F. Press, Guido Sauter, Marc Buyse, Leslie Bernstein, Roberta Guzman, Angela Santiago, Ivonne E. Villalobos, Wolfgang Eiermann, Tadeusz Pienkowski, Miguel Martin, Nicholas Robert, John Crown, Valerie Bee, Henry Taupin, Kerry J. Flom, Isabelle Tabah-Fisch, Giovanni Pauletti, Mary-Ann Lindsay, Alessandro Riva, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2010)

Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers.
Heterodimerization of Insulin-like Growth Factor Receptor/Epidermal Growth Factor Receptor and Induction of Survivin Expression Counteract the Antitumor Action of Erlotinib
Authors: Floriana Morgillo, Jong Kyu Woo, Edward S. Kim, Waun Ki Hong, Ho-Young Lee
Journal: Cancer Research (2006)

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat non–small cell lung cancer (NSCLC). However, the overall response rate to EGFR TKIs is limited, and the mechanisms mediating resistance to the drugs are poorly understood. Here, we report that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of erlotinib, an EGFR TKI. Treatment with erlotinib increased the levels of EGFR/IGF-IR heterodimer localized on cell membrane, activated IGF-IR and its downstream signaling mediators, and stimulated mammalian target of rapamycin (mTOR)–mediated de novo protein synthesis of EGFR and survivin in NSCLC cells. Inhibition of IGF-IR activation, suppression of mTOR-mediated protein synthesis, or knockdown of survivin expression abolished resistance to erlotinib and induced apoptosis in NSCLC cells in vitro and in vivo. Our data suggest that enhanced synthesis of survivin protein mediated by the IGFR/EGFR heterodimer counteracts the antitumor action of erlotinib, indicating the needs of integration of IGF-IR–targeted agents to the treatment regimens with EGFR TKI for patients with lung cancer. (Cancer Res 2006; 66(20): 10100-11)