tbuckley/cabot-search huggingface dataset:
Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies
Authors: Ting-Chao Chou
Journal: Pharmacological Reviews (2006)

The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for <i>n</i> drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI &lt; 1, = 1, and &gt; 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.
RIBBON-1: Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative, Locally Recurrent or Metastatic Breast Cancer
Authors: Nicholas J. Robert, Véronique Diéras, John Glaspy, Adam M. Brufsky, Igor Bondarenko, Oleg N. Lipatov, Edith A. Perez, Denise A. Yardley, Stephen Y.T. Chan, Xian Zhou, See-Chun Phan, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2011)

Purpose This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. Patients and Methods Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m 2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m 2 , docetaxel 75 or 100 mg/m 2 ), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks. BV or placebo was administered at 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), 1-year survival rate, objective response rate, duration of objective response, and safety. Two independently powered cohorts defined by the choice of chemotherapy (Cape patients or pooled Tax/Anthra patients) were analyzed in parallel. Results RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) enrolled 1,237 patients (Cape cohort, n = 615; Tax/Anthra cohort, n = 622). Median PFS was longer for each BV combination (Cape cohort: increased from 5.7 months to 8.6 months; hazard ratio [HR], 0.69; 95% CI, 0.56 to 0.84; log-rank P &lt; .001; and Tax/Anthra cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52 to 0.80; log-rank P &lt; .001). No statistically significant differences in OS between the placebo- and BV-containing arms were observed. Safety was consistent with results of prior BV trials. Conclusion The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.
Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma
Authors: Tarun Kewalramani, Andrew D. Zelenetz, Stephen D. Nimer, Carol Portlock, David Straus, Ariela Noy, Owen O'Connor, Daniel A. Filippa, Julie Teruya-Feldstein, Alison Gencarelli, Jing Qin, Alyson Waxman, Joachim Yahalom, Craig H. Moskowitz
Journal: Blood (2004)
An information resource linking performance to prevention of sports injuries - a preliminary inquiry
Authors: H Broughton, S Cromie, T Trimble
Journal: British Journal of Sports Medicine (2011)

Background A review by Chalmers et al. (2004), rugby coaches have a role in preventing injuries and a perspective by Bahr et al. (2005), understanding the mechanisms of injury in sport identified a number of factors. Objective To design an information resource for coaching sport. Design An information resource develops modules of learning, retrospective injury data are reviewed and ethical approval is sought. The inquiry is based on rugby union. Setting Structured interviews are held with senior level coaches. Participants Five qualified senior grade coaches in rugby union. Intervention The coaches remarked that safety is practicable, athlete conditioning beneficial and technique is important. Injury data linked to game events illustrated the relevance of Newtonian Physics. Results Qualitative data highlights safety as being practicable but game rules had less certainty. From the injury data the total consults: n=367 (08/09), n=377 (09/10) shoulder 39, 42; 81 due to the tackle (inertia &amp; interaction), low back 104, 41; 145 due to scrum, tackle (interaction), hamstring 38, 42; 80 due to running (inertia) and the ankle 52, 59;111 due to running, tackle (inertia). Conclusion Safety in coaching sport is practicable, but the game rules need more recognition. Applying Newtonian Physics to injury events enabled an understanding of game actions. Integrating into the modules of learning; the game rules, the applications of Newtonian Physics and attention to safety, injuries can be prevented.
Low intensity peripheral muscle conditioning improves exercise tolerance and breathlessness in COPD
Authors: CJ Clark, L Cochrane, E Mackay
Journal: European Respiratory Journal (1996)

This randomized, controlled study investigated the physiological effects of a specially designed 12 week programme of isolated conditioning of peripheral skeletal muscle groups. The programme required minimal infrastructure in order to allow continued rehabilitation at home after familiarization within hospital. Forty eight patients, aged 40-72 yrs with chronic obstructive pulmonary disease (COPD) (mean (SD) forced expiratory volume in one second (FEV1) 61 (27)% of predicted normal) were randomly allocated into training (n = 32) and control (n = 16) groups. Physiological assessments were performed before and after the 12 week study period, and included peripheral muscle endurance and strength, whole body endurance, maximal exercise capacity (maximum oxygen consumption (V'O2,max)) and lung function. The training group showed significant improvement in a variety of measures of upper and lower peripheral muscle performance, with no additional breathlessness. Whole body endurance measured by free arm treadmill walking increased by 6,372 (3,932-8,812) 3 (p &lt; 0.001). Symptom-limited maximal V'O2 was unchanged. However, the training group showed a reduction in ventilatory equivalents for oxygen and carbon dioxide, both at peak exercise and at equivalent work rate (Wmax). In summary, low intensity isolated peripheral muscle conditioning is well-tolerated, simple and easy to perform at home. The various physiological benefits should enable patients across the range of severity of chronic obstructive pulmonary disease to improve daily functioning.
Amplification of <i>CRKL</i> Induces Transformation and Epidermal Growth Factor Receptor Inhibitor Resistance in Human Non–Small Cell Lung Cancers
Authors: Hiu Wing Cheung, Jinyan Du, Jesse S. Boehm, Frank He, Barbara A. Weir, Xiaoxing Wang, Mohit Butaney, Lecia V. Sequist, Biao Luo, Jeffrey A. Engelman, David E. Root, Matthew Meyerson, Todd R. Golub, Pasi A. Jänne, William C. Hahn
Journal: Cancer Discovery (2011)

We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in epidermal growth factor receptor (EGFR)-mutant cells induces resistance to gefitinib by activating extracellular signal-regulated kinase and AKT signaling. We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.These studies credential CRKL as an oncogene in a subset of NSCLC. Overexpression of CRKL induces cell transformation and resistance to epidermal growth factor receptor inhibitor treatment and suggest that therapeutic interventions targeting CRKL may confer a clinical benefit in a defined subset of NSCLCs.
Nonadherence to Oral Mercaptopurine and Risk of Relapse in Hispanic and Non-Hispanic White Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group
Authors: Smita Bhatia, Wendy Landier, Muyun Shangguan, Lindsey Hageman, Alexandra N. Schaible, Andrea R. Carter, Cara L. Hanby, Wendy Leisenring, Yutaka Yasui, Nancy M. Kornegay, Leo Mascarenhas, A. Kim Ritchey, Jacqueline N. Casillas, David S. Dickens, Jane Meza, William L. Carroll, Mary V. Relling, F. Lennie Wong
Journal: Journal of Clinical Oncology (2012)

Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity.
Mesangial cells possess an asialoglycoprotein receptor with affinity for human immunoglobulin A.
Authors: C Gómez-Guerrero, N Duque, J Egido
Journal: Journal of the American Society of Nephrology (1998)

Asialoglycoprotein receptor (ASGP-R), a hepatic lectin involved in the clearance of galactose-terminal glycoproteins, is also present in extrahepatic tissues, but its expression in renal cells is not well established. This study examines the presence of ASGP-R in cultured mesangial cells (MC), key cells involved in the removal of macromolecules deposited in the glomerulus. The binding of asialo-orosomucoid (ASOR) to rat MC was saturable and galactose-specific. In addition, MC internalized and degraded ASOR in a Ca(2+)-dependent manner. Parallel studies were performed in a homologous system (human MC), obtaining similar binding curve and competition with unlabeled ASOR and carbohydrates. The purified receptor from rat MC consisted of two proteins (41 and 55 kD) with similar size to the hepatic receptor. Both subunits were detected by mRNA expression analysis (ratio 2:1). Because the hepatic receptor presents avidity for the carbohydrates of IgA1, a protein deposited in the glomerulus of patients with IgA nephropathy, the interaction of IgA1 with the mesangial ASGP-R was explored. As for the interaction with ASOR, catabolism of IgA1 by rat and human MC was Ca(2+)-dependent and was reduced with galactose. In addition, the interaction of ASOR with rat MC was partially inhibited by incubation with IgA1 and its desialylated form, but not by IgA2, as demonstrated in binding experiments and in receptor purification. It is concluded that MC possess ASGP-R specific for galactose residues of several glycoproteins, including IgA1. These data could be important for a better understanding of the pathogenesis of IgA nephropathy.
Selection to Maintain Paralogous Amino Acid Differences Under the Pressure of Gene Conversion in the Heat-Shock Protein Genes in Yeast
Authors: Shohei Takuno, Hideki Innan
Journal: Molecular Biology and Evolution (2009)

A genome scan for the signatures of selection for paralogous functional amino acid differences was performed with yeast genomes. This recently developed method makes it possible to localize the target sites of selection under the pressure of gene conversion. We found that two gene pairs have strong signatures of selection. The two pairs of duplicated genes happened to be heat shock genes (Ssa1/ Ssa2 and Ssb1/Ssb2), which have similar protein structures to each other, although the amino acid sequence identity between Ssa and Ssb is not high (∼60%). Interestingly, the two gene pairs exhibit signature of selection at almost identical positions within the substrate-binding domain β. Because this domain specifies the substrate polypeptides, it is presumed that functional divergence may be advantageous in this domain. Evolutionary analysis demonstrated that the observed divergence in the two gene pairs has been maintained in many yeast species independently, suggesting long-term operation of strong selection.
Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach
Authors: Fatih Tanriverdi, Harald Jörn Schneider, Gianluca Aimaretti, Brent E. Masel, Felipe F. Casanueva, Fahrettin Kelestimur
Journal: Endocrine Reviews (2015)

Traumatic brain injury (TBI) is a growing public health problem worldwide and is a leading cause of death and disability. The causes of TBI include motor vehicle accidents, which are the most common cause, falls, acts of violence, sports-related head traumas, and war accidents including blast-related brain injuries. Recently, pituitary dysfunction has also been described in boxers and kickboxers. Neuroendocrine dysfunction due to TBI was described for the first time in 1918. Only case reports and small case series were reported until 2000, but since then pituitary function in TBI victims has been investigated in more detail. The frequency of hypopituitarism after TBI varies widely among different studies (15–50% of the patients with TBI in most studies). The estimates of persistent hypopituitarism decrease to 12% if repeated testing is applied. GH is the most common hormone lost after TBI, followed by ACTH, gonadotropins (FSH and LH), and TSH. The underlying mechanisms responsible for pituitary dysfunction after TBI are not entirely clear; however, recent studies have shown that genetic predisposition and autoimmunity may have a role. Hypopituitarism after TBI may have a negative impact on the pace or degree of functional recovery and cognition. What is not clear is whether treatment of hypopituitarism has a beneficial effect on specific function. In this review, the current data related to anterior pituitary dysfunction after TBI in adult patients are updated, and guidelines for the diagnosis, follow-up strategies, and therapeutic approaches are reported.
Rapid and Efficient Differentiation of Human Pluripotent Stem Cells into Intermediate Mesoderm That Forms Tubules Expressing Kidney Proximal Tubular Markers
Authors: Albert Q. Lam, Benjamin S. Freedman, Ryuji Morizane, Paul H. Lerou, M. Todd Valerius, Joseph V. Bonventre
Journal: Journal of the American Society of Nephrology (2013)

Human pluripotent stem cells (hPSCs) can generate a diversity of cell types, but few methods have been developed to derive cells of the kidney lineage. Here, we report a highly efficient system for differentiating human embryonic stem cells and induced pluripotent stem cells (referred to collectively as hPSCs) into cells expressing markers of the intermediate mesoderm (IM) that subsequently form tubule-like structures. Treatment of hPSCs with the glycogen synthase kinase-3β inhibitor CHIR99021 induced BRACHYURY(+)MIXL1(+) mesendoderm differentiation with nearly 100% efficiency. In the absence of additional exogenous factors, CHIR99021-induced mesendodermal cells preferentially differentiated into cells expressing markers of lateral plate mesoderm with minimal IM differentiation. However, the sequential treatment of hPSCs with CHIR99021 followed by fibroblast growth factor-2 and retinoic acid generated PAX2(+)LHX1(+) cells with 70%-80% efficiency after 3 days of differentiation. Upon growth factor withdrawal, these PAX2(+)LHX1(+) cells gave rise to apically ciliated tubular structures that coexpressed the proximal tubule markers Lotus tetragonolobus lectin, N-cadherin, and kidney-specific protein and partially integrated into embryonic kidney explant cultures. With the addition of FGF9 and activin, PAX2(+)LHX1(+) cells specifically differentiated into cells expressing SIX2, SALL1, and WT1, markers of cap mesenchyme nephron progenitor cells. Our findings demonstrate the effective role of fibroblast growth factor signaling in inducing IM differentiation in hPSCs and establish the most rapid and efficient system whereby hPSCs can be differentiated into cells with features characteristic of kidney lineage cells.
Heart-stopping antibodies
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Women with lupus and rheumatoid arthritis are at increased risk for having babies with congenital heart block, and maternal autoantibodies that cross the placenta are thought to be the main cause. On page 11, Salomonsson et al. show that a subset of autoantibodies that disrupt the calcium homeostasis in heart cells is responsible.Women with autoantibodies specific for an intracellular protein of unknown function called SSA/Ro52 (Ro52) are more likely to have babies with congenital heart block—a condition in which the electrical impulses that regulate the heart beat are disrupted. The pathogenic response has been associated with the presence of antibodies that bind to one peptide on Ro52 called p200, but the mechanism was until recently a mystery.






Figure 

Autoantibodies cause calcium (blue) to accumulate in rat heart cells.




The authors have now pinpointed the pathogenic response even further by showing that not all p200-specific antibodies cause disease. They cloned two antibodies from rheumatic patients, which both recognized p200 but had distinct binding properties. One of these antibodies, but not the other, bound to neonatal rat heart cells and deregulated calcium homeostasis. Intracellular calcium accumulated in these cells, eventually triggering apoptosis. When sera from newborn children with congenital heart block were analyzed, there was a predominance of antibodies with binding properties similar to those of the pathogenic subset of p200-specific maternal antibodies.

The mechanism by which these antibodies interfere with normal calcium flux remains unsolved. The authors believe that in vivo the p200-specific antibodies bind not to intracellular Ro52 but to a cross-reacting protein on the cell surface. They are now trying to identify that protein but meanwhile hope that this study will provide a new way to identify women who are most at risk for having children with congenital heart block.
Can measurement of peak expiratory flow enhance compliance in chronic asthma?
Authors: I Gregg
Journal: European Respiratory Journal (1992)

Almost all patients with chronic asthma will derive benefit from self-measurement of PEF. Unquestionably, this is of value for educating patients about their disease and treatment, leading in turn to improved compliance. It will be several years before it becomes clear what proportion of patients are willing to manage their asthma themselves and are sufficiently competent in the interpretation of their measurement of PEF to do so safely. It remains to be seen what effect greater use of PEF measurement by patients will have upon present levels of morbidity and mortality from asthma.
Antibiotic Treatment Is Not Effective in Patients Infected With <i>Helicobacter pylori</i> Suffering From Extragastric MALT Lymphoma
Authors: Birgit Grünberger, Stefan Wöhrer, Berthold Streubel, Michael Formanek, Ventzislav Petkov, Andreas Puespoek, Michael Haefner, Michael Hejna, Ulrich Jaeger, Andreas Chott, Markus Raderer
Journal: Journal of Clinical Oncology (2006)

Purpose Apart from anecdotal reports implicating Helicobacter pylori (HP) in the development of extragastric mucosa associated lymphoid tissue (MALT) lymphoma, no large scale prospective studies have been performed on this topic. Patients and Methods A total of 77 patients with extragastric MALT lymphoma were prospectively studied. The presence or absence of HP was tested by histology, urease breath test, and serology. Patients were also tested for hepatitis A, B, and C and autoimmune conditions along with assessment of MALT lymphoma-specific genetic changes. Results Evidence for infection with HP was present in 35 of 77 patients (45%), and three of 75 patients tested (4%) were positive for hepatitis C and one for hepatitis B. All patients with HP-infection underwent eradication, 16 before initiation of further therapy. Apart from one patient with lymphoma involving parotid and colon, who achieved regression of the colonic lesions, none of these 16 patients showed regression of the lymphoma after a median follow-up of 14 months (range, 8 to 48+ months) before initiation of definitive treatment. No correlation between HP-status, localization, stage, autoimmune diseases, and genetic findings was seen. Conclusion In our series, HP-eradication was ineffective for treatment of extragastric MALT lymphomas. This finding, along with an infection rate of 45%—as could also be expected in the general Austrian population—suggests that HP does not play a role in the development of these lymphomas. Antibiotic treatment targeting HP should, therefore, be discouraged in patients with extragastric MALT lymphomas.