tbuckley/cabot-search huggingface dataset:
Increased surface expression of CD11b/CD18 (Mac-1) is not required for stimulated neutrophil adherence to cultured endothelium.
Authors: N B Vedder, J M Harlan
Journal: Journal of Clinical Investigation (1988)

The mechanism whereby the human neutrophil membrane heterodimer, CD11b/CD18 (Mac-1, Mo1), mediates neutrophil adherence is not known. We studied the role of CD11b/CD18 surface expression in the promotion of neutrophil adhesiveness. We found that phorbol myristate acetate (PMA), calcium ionophore (A23187), and FMLP caused a three- to sevenfold increase in surface expression of both CD11b (alpha M) and CD18 (beta) as assayed by binding of MAbs 60.1 (anti-CD11b) and 60.3 (anti-CD18). Increased binding of MAbs was temporally associated with the promotion of neutrophil aggregation and adherence to cultured endothelial monolayers. Pretreatment of neutrophils with the anion channel-blocking agent, DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid), inhibited the increased surface expression of CD11b and CD18 after stimulation by PMA, A23187, or FMLP and resulted in nearly complete inhibition of neutrophil aggregation. However, pretreatment with DIDS did not diminish either PMA-, A23187-, or FMLP-stimulated neutrophil adherence to endothelial monolayers. We also observed that stimulation of granule-depleted neutrophil cytoplasts by PMA, A23187, or FMLP induced aggregation and adherence to endothelial monolayers without increasing surface expression of CD11b or CD18. We conclude that the increased surface expression of CD11b/CD18 that occurs after stimulation is neither sufficient nor necessary for enhanced adherence to endothelium. Moreover, though both are CD11b/CD18-dependent, the mechanisms involved in neutrophil aggregation are different from those involved in neutrophil adherence to endothelium.
Replication-competent Herpes Simplex Virus Retargeted to HER2 as Therapy for High-grade Glioma
Authors: Eleonora Gambini, Elisa Reisoli, Irene Appolloni, Valentina Gatta, Gabriella Campadelli-Fiume, Laura Menotti, Paolo Malatesta
Journal: Molecular Therapy (2012)

Oncolytic herpes simplex viruses (HSVs) represent a novel frontier against tumors resistant to standard therapies, like glioblastoma (GBM). The oncolytic HSVs that entered clinical trials so far showed encouraging results; however, they are marred by the fact that they are highly attenuated. We engineered HSVs that maintain unimpaired lytic efficacy and specifically target cells that express tumor-specific receptors, thus limiting the cytotoxicity only to cancer cells, and leaving unharmed the neighboring tissues. We report on the safety and efficacy in a high-grade glioma (HGG) model of R-LM113, an HSV recombinant retargeted to human epidermal growth factor receptor 2 (HER2), frequently expressed in GBMs. We demonstrated that R-LM113 is safe in vivo as it does not cause encephalitis when intracranially injected in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, extremely sensitive to wild-type HSV. The efficacy of R-LM113 was assessed in a platelet-derived growth factor (PDGF)-induced infiltrative glioma model engineered to express HER2 and transplanted intracranially in adult NOD/SCID mice. Mice injected with HER2-engineered glioma cells infected with R-LM113 showed a doubled survival time compared with mice injected with uninfected cells. A doubling in survival time from the beginning of treatment was obtained also when R-LM113 was administered into already established tumors. These data demonstrate the efficacy of R-LM113 in thwarting tumor growth.
A–Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance: Part 41
Authors: M K Ranchordas, B Lundy, L M Burke, S J Stear, L M Castell
Journal: British Journal of Sports Medicine (2013)

Vitamin preparations have been a stalwart of the supplement industry. They reflect both our understanding that they are, by definition, essential for optimal health and function, as well as our fears that either the food supply, or the way we consume it, fails to provide us with optimal amounts of these micronutrients. In the case of B-vitamins, the greatest research interest in supplementation occurred around World War II, tied to the reasonably new discovery of many of these vitamins and the interest in adequate war rations and military feeding plans. Even with the more targeted interest in sports nutrition, the topic of vitamin supplementation seems dated, with most available studies dating back to the early 1990s. The interest in vitamin K in sports nutrition, however, is more contemporary, due to its role in bone health.

### M K Ranchordas

The B-vitamins are water-soluble vitamins that play crucial roles in energy metabolism. There are eight B-vitamins: thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5) pyridoxine (B6), biotin (B7), involved in energy-producing pathways; folic acid (B9), cobalamin (B12) involved in synthesising new cells, red blood cells and in cell repair. The richest sources of B-vitamins are unprocessed foods such as whole grains, green leafy vegetables, nuts, dairy products and animal foods such as meat and eggs but, in many countries, foods such as cereals and bread are fortified with these vitamins.

It has been reported that inadequate intake and deficiencies in B-vitamins could impair athletic performance.1 ,2 Studies examining dietary intakes of B-vitamins in …
Comparative Efficacy of Intracoronary Allogeneic Mesenchymal Stem Cells and Cardiosphere-Derived Cells in Swine with Hibernating Myocardium
Authors: Brian R. Weil, Gen Suzuki, Merced M. Leiker, James A. Fallavollita, John M. Canty
Journal: Circulation Research (2015)

Rationale: Allogeneic bone marrow–derived mesenchymal stem cells (MSCs) and cardiosphere-derived cells (CDCs) have each entered clinical trials, but a direct comparison of these cell types has not been performed in a large animal model of hibernating myocardium. Objective: Using completely blinded methodology, we compared the efficacy of global intracoronary allogeneic MSCs (icMSCs, ≈35×10 6 ) and CDCs (icCDCs, ≈35×10 6 ) versus vehicle in cyclosporine-immunosuppressed swine with a chronic left anterior descending coronary artery stenosis (n=26). Methods and Results: Studies began 3 months after instrumentation when wall thickening was reduced (left anterior descending coronary artery % wall thickening [mean±SD], 38±11% versus 83±26% in remote; P &lt;0.01) and similar among groups. Four weeks after treatment, left anterior descending coronary artery % wall thickening increased similarly after icCDCs and icMSCs, whereas it remained depressed in vehicle-treated controls (icMSCs, 51±13%; icCDCs, 51±17%; vehicle, 34±3%, treatments P &lt;0.05 versus vehicle). There was no change in myocardial perfusion. Both icMSCs and icCDCs increased left anterior descending coronary artery myocyte nuclear density (icMSCs, 1601±279 nuclei/mm 2 ; icCDCs, 1569±294 nuclei/mm 2 ; vehicle, 973±181 nuclei/mm 2 ; treatments P &lt;0.05 versus vehicle) and reduced myocyte diameter (icMSCs, 16.4±1.5 μm; icCDCs, 16.8±1.2 μm; vehicle, 20.2±3.7 μm; treatments P &lt;0.05 versus vehicle) to the same extent. Similar changes in myocyte nuclear density and diameter were observed in the remote region of cell-treated animals. Cell fate analysis using Y-chromosome fluorescent in situ hybridization demonstrated rare cells from sex-mismatched donors. Conclusions: Allogeneic icMSCs and icCDCs exhibit comparable therapeutic efficacy in a large animal model of hibernating myocardium. Both cell types produced equivalent increases in regional function and stimulated myocyte regeneration in ischemic and remote myocardium. The activation of endogenous myocyte proliferation and regression of myocyte cellular hypertrophy support a common mechanism of cardiac repair.
Common ground on which to approach the origins of higher cognition
Authors: Richard W. Byrne, Anne E. Russon
Journal: Behavioral and Brain Sciences (1998)

Imitation research has been hindered by (1) overly molecular analyses of behaviour that ignore hierarchical structure, and (2) attempts to disqualify observational evidence. Program-level imitation is one of a range of cognitive skills for scheduling efficient novel behaviour, in particular, enabling an individual to purloin the organization of another's behaviour for its own. To do so, the individual must perceive the underlying hierarchical schedule of the fluid action it observes and must understand the local functions of subroutines within the overall goal-directed process. Action-level imitation, copying strings of actions linearly without any such understanding, is less valuable for acquiring complex behaviour and may often have other, social functions. At present, we lack a mechanistic understanding of the abilities underlying program-level imitation that make it possible for the underlying structure of complex actions to be dissected visually and recreated in behaviour.
Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non–Small-Cell Lung Cancer
Authors: Toshimi Takano, Yuichiro Ohe, Hiromi Sakamoto, Koji Tsuta, Yoshihiro Matsuno, Ukihide Tateishi, Seiichiro Yamamoto, Hiroshi Nokihara, Noboru Yamamoto, Ikuo Sekine, Hideo Kunitoh, Tatsuhiro Shibata, Tokuki Sakiyama, Teruhiko Yoshida, Tomohide Tamura
Journal: Journal of Clinical Oncology (2005)

To evaluate epidermal growth factor receptor (EGFR) mutations and copy number as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib.Sixty-six patients with NSCLC who experienced relapse after surgery and received gefitinib were included. Direct sequencing of exons 18 to 24 of EGFR and exons 18 to 24 of ERBB2 was performed using DNA extracted from surgical specimens. Pyrosequencing and quantitative real-time polymerase chain reaction were performed to analyze the allelic pattern and copy number of EGFR.Thirty-nine patients (59%) had EGFR mutations; 20 patients had deletional mutations in exon 19, 17 patients had missense mutations (L858R) in exon 21, and two patients had missense mutations (G719S or G719C) in exon 18. No mutations were identified in ERBB2. Response rate (82% [32 of 39 patients] v 11% [three of 27 patients]; P < .0001), time to progression (TTP; median, 12.6 v 1.7 months; P < .0001), and overall survival (median, 20.4 v 6.9 months; P = .0001) were significantly better in patients with EGFR mutations than in patients with wild-type EGFR. Increased EGFR copy numbers (> or = 3/cell) were observed in 29 patients (44%) and were significantly associated with a higher response rate (72% [21 of 29 patients] v 38% [14 of 37 patients]; P = .005) and a longer TTP (median, 9.4 v 2.6 months; P = .038). High EGFR copy numbers (> or = 6/cell) were caused by selective amplification of mutant alleles.EGFR mutations and increased copy numbers were significantly associated with better clinical outcome in gefitinib-treated NSCLC patients.
Determinants of the prognosis after a first myocardial infarction in a migrant Japanese population. The Honolulu Heart Program.
Authors: K Yano, J S Grove, D M Reed, H M Chun
Journal: Circulation (1993)

Although numerous studies have been published on the prognostic assessment of myocardial infarction, little is known about determinants of the prognosis after a first myocardial infarction, especially regarding the role of standard risk factors for coronary heart disease (CHD) measured before the development of myocardial infarction.In a prospective study of CHD among men of Japanese ancestry living in Hawaii, 457 patients with a first myocardial infarction (age range, 46 to 84 years) were identified during 20 years of follow-up. The relations of clinical variables and CHD risk factors to mortality in early (< 30 days) and two stages of late (30 days to 5 years and 5 to 10 years) periods after myocardial infarction in these patients were investigated. In multivariate analyses using logistic regression models (for early mortality) and Cox regression models (for late mortality), age at myocardial infarction and severe complications (Killip classes 3 and 4) were independent predictors of both early and late mortality (up to 5 years after myocardial infarction). In addition, ventricular arrhythmias predicted only early mortality, whereas anterior myocardial infarction, radiological evidence of cardiomegaly and/or pulmonary congestion, and intraventricular block predicted only late mortality (up to 5 years after myocardial infarction). Only age was an independent predictor of all-cause mortality more than 5 years after myocardial infarction. After adjusting for age at myocardial infarction and these clinical variables, preinfarction-measured risk factors such as 1-hour postload serum glucose (positively) and 1-second forced expiratory volume (inversely) were significantly associated with late mortality up to 5 years, whereas systolic blood pressure was the only independent predictor of late mortality after 5 years.This study has confirmed the importance of age at myocardial infarction and clinical indicators of complications such as Killip class 3 or 4, radiological evidence of pulmonary congestion, and ventricular arrhythmias or intraventricular block as the prognostic determinants of myocardial infarction. In addition, some of the preinfarction-measured standard risk factors for CHD were found to predict long-term prognosis independent of age and clinical factors.
Hemoglobin aggregation and pseudosickling in vitro of hemoglobin setif‐containing erythrocytes
Authors: C. T. Noguchi, N. Mohandas, J. Blanchette‐Mackie, S. Mackie, E. Raik, S. Charache
Journal: American Journal of Hematology (1991)

Abstract Erythrocytes from individuals heterozygous for hemoglobin Setif (α 94 Asp→Tyr) sickle in vitro without deoxygenation when incubated in chloride buffer due to hemoglobin aggregation. We now report quantitative studies of hemoglobin polymerization and deformability in these cells. Hemoglobin polymer gradually increased in intact cells during a 24 h incubation period at 24°C. After 24 hr, about 80% of the cells in 290 mosm sodium chloride buffer contained polymer which appeared as short rods compared to &gt;99% containing polymer at 450 mOsm. Similar proportions of cells were morphologically sickled. Deformability of erythrocytes with 40% hemoglobin Setif incubated in 290 mOsm buffer at 37°C decreased to 80% of normal by 210 min but in 450 mOsm decreased to 50% after only 30 min as measured by the ektacytometer. However, at 4°C deformability remained normal even in 450 mOsm buffer. The solubility of gelled hemolysate containing 40% hemoglobin Setif was 24 g/dl and 21 g/dl at 290 and 459 mOsm buffer respectively. The gel persisted at 4°C with a solubility of 25 g/dl, but melted when dialyzed into sodium phosphate or potassium phosphate buffer. These data suggest that hemoglobin polymerization, reduced deformability, and sickling of hemoglobin Setif‐containing erythrocytes are related to reduced hemoglobin solubility. The rate and extent of intracellular polymerization in vitro are considerably reduced (as in the case of sickle trait) compared with erythrocytes from individuals with sickle cell anemia. Hence, the slower kinetics of hemoglobin aggregation in hemoglobin Setif‐containing cells provide an alternate system for studying hemoglobin aggregation in hemoglobin Setif‐containing cells provide an alternate system for studying hemoglobin polymerization and abnormal rhelogy.
Same day versus split dose bowel preparation for afternoon colonoscopy: impact on mucosal visibility and patient quality of life
Authors: G. Longcroft-Wheaton, P. Bhandari
Journal: Gut (2011)

<h3>Introduction</h3> Conventional bowel preparation for afternoon colonoscopy involves the use of an oral agent the day prior to the procedure, with further preparation on the morning of the procedure. We hypothesise that for afternoon lists same day bowel prep would be more effective, avoiding a wasted day taking bowel prep and could lead to a cleaner bowel. <h3>Methods</h3> Using nationally accepted criteria we compared the recorded quality of bowel preparation. All procedures were performed by the same endoscopist on an afternoon list. Group A consisted of patients prepared with three sachets of picolax, given at 12:00 and 17:00 the day before, and at 8:00 on the morning of the procedure. Group B consisted of patients given two sachets of picolax on the morning of the procedure at 07:00 and 10:00. A Fisher9s exact test was performed to test for a significant difference in mucosal visibility between the regimes. Polyp detection, sedation levels and patient comfort was compared between the groups. Patients completed a quality of life (QOL) questionnaire investigating complications, including faecal incontinence, interruption to sleep, headaches, vomiting, abdominal pain, impact on work and social activities and preference of regime. <h3>Results</h3> There were 214 patients, 82 in group A and 132 in group B. 70% were male, median age 65 (range 60–71). 66% had polyps. There was no difference in sedation or discomfort between the groups. Same day preparation produced better mucosal visibility than the split dose regimen (p = 0.0046). See table 1. Polyp detection in the same day regimen was numerically better (71% vs 62%) but the study was not powered to show statistical difference (p = 0.2). QOL questionnaires were completed by 92 patients. There was less faecal incontinence, interruption to sleep, headaches, vomiting or abdominal pain with same day prep (P = 0.0001). Patients in the same day regimen reported less impact on ADLs compared to split dose prep. For the whole cohort patients favoured choice for preparation was for the same day regimen (p = 0.037). Amongst the split dose patients 40% favoured split dose, 48% same day prep with 12% unsure (P = 0.57). Amongst the same day prep patients 14% favoured split dose, 83% favoured same day prep with 3% unsure (p = 0.0001). The difference between the groups was significant (P = 0.004). <h3>Conclusion</h3> We found that afternoon colonoscopy with same day bowel preparation is feasible, safe and more effective than the conventional split dose regime. Patients preferred the same day regimen and it has less impact on QOL with less adverse effects. We believe same day bowel prep should become a new standard for afternoon colonoscopy.
Enhanced Immune System Regeneration in Humans Following Allogeneic or Autologous Hemopoietic Stem Cell Transplantation by Temporary Sex Steroid Blockade
Authors: Jayne S. Sutherland, Lisa Spyroglou, Jennifer L. Muirhead, Tracy S. Heng, Adria Prieto-Hinojosa, H. Miles Prince, Ann P. Chidgey, Anthony P. Schwarer, Richard L. Boyd
Journal: Clinical Cancer Research (2008)

To determine if temporarily blocking sex steroids prior to stem cell transplantation can increase thymus function and thus enhance the rate of T cell regeneration.This was a pilot study of luteinizing hormone-releasing hormone agonist (LHRH-A) goserelin given 3 weeks prior to allogeneic or autologous hemopoietic stem cell transplantation and administered up to 3 months posttransplantation. Patients (with or without LHRH-A administration) were assessed from 1 week to 12 months posttransplantation for multiple immunologic variables by flow cytometry (particularly naïve T cells), quantitative PCR to assess T-cell receptor excision circle levels (as a correlate of thymus function), CDR3 length analysis to determine the variability of the TCR repertoire, and in vitro assays to determine functional T cell responses.LHRH-A administration prior to stem cell transplantation significantly increased neutrophil and lymphocyte numbers within the first month of posttransplantation. Most importantly, total and naïve CD4(+) T cell regeneration together with T-cell receptor excision circle production, T cell repertoire regeneration, and peripheral T cell function were also significantly enhanced at multiple time points posttransplant. In addition, an increase in disease-free survival (P = 0.04) was seen in the autologous setting. Although LHRH-A administration increased T cell responses in vitro, it did not exacerbate graft-versus-host disease in the allogeneic setting.This study provides an important new approach to the improvement of immune reconstitution in patients undergoing hemopoietic stem cell transplantation and may have generic applications in many T cell-based disorders.
Parallel analysis of RNA ends enhances global investigation of microRNAs and target RNAs of Brachypodium distachyon
Authors: Dong-Hoon Jeong, Skye A Schmidt, Linda A Rymarquis, Sunhee Park, Matthias Ganssmann, Marcelo A German, Monica Accerbi, Jixian Zhai, Noah Fahlgren, Samuel E Fox, David F Garvin, Todd C Mockler, James C Carrington, Blake C Meyers, Pamela J Green
Journal: Genome biology (2013)

The wild grass Brachypodium distachyon has emerged as a model system for temperate grasses and biofuel plants. However, the global analysis of miRNAs, molecules known to be key for eukaryotic gene regulation, has been limited in B. distachyon to studies examining a few samples or that rely on computational predictions. Similarly an in-depth global analysis of miRNA-mediated target cleavage using parallel analysis of RNA ends (PARE) data is lacking in B. distachyon. B. distachyon small RNAs were cloned and deeply sequenced from 17 libraries that represent different tissues and stresses. Using a computational pipeline, we identified 116 miRNAs including not only conserved miRNAs that have not been reported in B. distachyon, but also non-conserved miRNAs that were not found in other plants. To investigate miRNA-mediated cleavage function, four PARE libraries were constructed from key tissues and sequenced to a total depth of approximately 70 million sequences. The roughly 5 million distinct genome-matched sequences that resulted represent an extensive dataset for analyzing small RNA-guided cleavage events. Analysis of the PARE and miRNA data provided experimental evidence for miRNA-mediated cleavage of 264 sites in predicted miRNA targets. In addition, PARE analysis revealed that differentially expressed miRNAs in the same family guide specific target RNA cleavage in a correspondingly tissue-preferential manner. B. distachyon miRNAs and target RNAs were experimentally identified and analyzed. Knowledge gained from this study should provide insights into the roles of miRNAs and the regulation of their targets in B. distachyon and related plants.
Ebola: evaluating vaccines during epidemics
Authors: Chee Fu Yung
Journal: BMJ (2015)

Innovative, flexible, and validated study designs need to be ready for next time

Will vaccines be effective? Would trials be ethical? Are trials even required? These are some of the questions that dominated health policy discourse throughout the current Ebola tragedy in West Africa. The epidemic of Ebola viral disease resulted in almost 27 000 cases, more than 11 000 deaths, and crippled already weak public health infrastructures.1 The welcome reduction in numbers of cases has, however, produced another conundrum and highlighted the challenges in evaluating the efficacy of vaccines in the middle of unpredictable epidemics. The linked paper by the Ebola ca suffit ring vaccination trial consortium (doi:10.1136/bmj.h3740) describes a novel trial design using “ring vaccination” to test one of the early Ebola vaccine candidates (rVSV-ZEBOV) in Guinea.2 The dwindling number of cases means that phase III studies may not have enough power to demonstrate or rule out efficacy using the gold standard of individual randomisation trials.3 Since we still do not have markers for correlates of protection against the Ebola virus, we need efficacy studies …