tbuckley/cabot-search huggingface dataset:
PET Imaging of Integrin αVβ3 Expression
Authors: Ambros J. Beer, Horst Kessler, Hans-Jürgen Wester, Markus Schwaiger
Journal: Theranostics (2011)

PET imaging of integrin αvβ3 expression has been studied intensely by the academia and recently also by the industry. Imaging of integrin αvβ3 expression is of great potential value, as the integrin αvβ3 is a key player in tumor metastasis and angiogenesis. Therefore PET imaging of this target might be a suitable in-vivo biomarker of angiogenesis and metastatic potential of tumors. In this manuscript, the various strategies for PET imaging of the integrin αvβ3 will be summarized, including monomeric and multimeric radiolabelled RGD peptides and nanoparticles. While most experiments have been performed using preclinical tumor models, more and more clinical results on PET imaging of αvβ3 expression are available and will be discussed in detail. However, while a multitude of radiotracer strategies have been successfully evaluated for PET imaging of αvβ3, the ultimate clinical value of this new imaging biomarker still has to be evaluated in large clinical trials.
NH2-terminal sequence of macrophage-expressed natural resistance-associated macrophage protein (Nramp) encodes a proline/serine-rich putative Src homology 3-binding domain.
Authors: C H Barton, J K White, T I Roach, J M Blackwell
Journal: The Journal of Experimental Medicine (1994)

The Lsh/Ity/Bcg locus on mouse chromosome 1 regulates macrophage (m phi) priming/activation for antimicrobial activity against intracellular pathogens. A candidate Bcg gene, designated natural resistance-associated m phi protein (Nramp), recently isolated from a pre-B cell cDNA library encodes a polytopic integral membrane protein with structural features common to prokaryotic and eukaryotic transporters. In the present study, an activated m phi cDNA library yielded new Nramp clones that differ in the 5' region from the published pre-B cell-derived clone sequence, resulting in addition of 64 amino acids at the NH2 terminus of the predicted protein. This new domain is rich in proline, serine, and basic amino acids, and includes three protein kinase C phosphorylation sites and a putative Src homology 3 binding domain. RNAs containing this domain are the only form found in the m phi. Hence, the protein encoded by this RNA is the candidate molecule mediating natural resistance to intra-m phi pathogens.
Activation of Coagulation Factor V by a Platelet Protease
Authors: William H. Kane, Jozef S. Mruk, Philip W. Majerus
Journal: Journal of Clinical Investigation (1982)

Factor V must be converted to Factor Va in order to bind to a high affinity platelet surface site and participate in prothrombin activation. Osterud et al. (10) presented data that suggested that human platelets contain an activated form of Factor V and a Factor V activator. We find that the Factor V released when platelets are disrupted by freezing and thawing or sonication is activated 3- to 10-fold by thrombin as determined by coagulation assay and is therefore stored as the relatively inactive procofactor rather than in the active form Factor Va.
Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis
Authors: A. L D'Souza
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To evaluate efficacy of probiotics in prevention and treatment of diarrhoea associated with the use of antibiotics. <b>Design:</b> Meta-analysis; outcome data (proportion of patients not getting diarrhoea) were analysed, pooled, and compared to determine odds ratios in treated and control groups. <b>Identification:</b> Studies identified by searching Medline between 1966 and 2000 and the Cochrane Library. Studies reviewed Nine randomised, double blind, placebo controlled trials of probiotics. <b>Results:</b> Two of the nine studies investigated the effects of probiotics in children. Four trials used a yeast (<i>Saccharomyces boulardii)</i>, four used lactobacilli, and one used a strain of enterococcus that produced lactic acid. Three trials used a combination of probiotic strains of bacteria. In all nine trials, the probiotics were given in combination with antibiotics and the control groups received placebo and antibiotics. The odds ratio in favour of active treatment over placebo in preventing diarrhoea associated with antibiotics was 0.39 (95% confidence interval 0.25 to 0.62; P&lt;0.001) for the yeast and 0.34 (0.19 to 0.61; P&lt;0.01 for lactobacilli. The combined odds ratio was 0.37 (0.26 to 0.53; P&lt;0.001) in favour of active treatment over placebo. <b>Conclusions:</b> The meta-analysis suggests that probiotics can be used to prevent antibiotic associated diarrhoea and that <i>S boulardii</i> and lactobacilli have the potential to be used in this situation. The efficacy of probiotics in treating antibiotic associated diarrhoea remains to be proved. A further large trial in which probiotics are used as preventive agents should look at the costs of and need for routine use of these agents.
Parallel Evolution of Nacre Building Gene Sets in Molluscs
Authors: Daniel J. Jackson, Carmel McDougall, Ben Woodcroft, Patrick Moase, Robert A. Rose, Michael Kube, Richard Reinhardt, Daniel S. Rokhsar, Caroline Montagnani, Caroline Joubert, David Piquemal, Bernard M. Degnan
Journal: Molecular Biology and Evolution (2009)

The capacity to biomineralize is closely linked to the rapid expansion of animal life during the early Cambrian, with many skeletonized phyla first appearing in the fossil record at this time. The appearance of disparate molluscan forms during this period leaves open the possibility that shells evolved independently and in parallel in at least some groups. To test this proposition and gain insight into the evolution of structural genes that contribute to shell fabrication, we compared genes expressed in nacre (mother-of-pearl) forming cells in the mantle of the bivalve Pinctada maxima and the gastropod Haliotis asinina. Despite both species having highly lustrous nacre, we find extensive differences in these expressed gene sets. Following the removal of housekeeping genes, less than 10% of all gene clusters are shared between these molluscs, with some being conserved biomineralization genes that are also found in deuterostomes. These differences extend to secreted proteins that may localize to the organic shell matrix, with less than 15% of this secretome being shared. Despite these differences, H. asinina and P. maxima both secrete proteins with repetitive low-complexity domains (RLCDs). Pinctada maxima RLCD proteins-for example, the shematrins-are predominated by silk/fibroin-like domains, which are absent from the H. asinina data set. Comparisons of shematrin genes across three species of Pinctada indicate that this gene family has undergone extensive divergent evolution within pearl oysters. We also detect fundamental bivalve-gastropod differences in extracellular matrix proteins involved in mollusc-shell formation. Pinctada maxima expresses a chitin synthase at high levels and several chitin deacetylation genes, whereas only one protein involved in chitin interactions is present in the H. asinina data set, suggesting that the organic matrix on which calcification proceeds differs fundamentally between these species. Large-scale differences in genes expressed in nacre-forming cells of Pinctada and Haliotis are compatible with the hypothesis that gastropod and bivalve nacre is the result of convergent evolution. The expression of novel biomineralizing RLCD proteins in each of these two molluscs and, interestingly, sea urchins suggests that the evolution of such structural proteins has occurred independently multiple times in the Metazoa.
Assessment of Low Linear Energy Transfer Radiation–Induced Bystander Mutagenesis in a Three-Dimensional Culture Model
Authors: Rudranath Persaud, Hongning Zhou, Sarah E. Baker, Tom K. Hei, Eric J. Hall
Journal: Cancer Research (2005)

Abstract A three-dimensional cell culture model composed of human-hamster hybrid (AL) and Chinese hamster ovary (CHO) cells in multicellular clusters was used to investigate low linear energy transfer (LET) radiation–induced bystander genotoxicity. CHO cells were mixed with AL cells in a 1:5 ratio and briefly centrifuged to produce a spheroid of 4 × 106 cells. CHO cells were labeled with tritiated thymidine ([3H]dTTP) for 12 hours and subsequently incubated with AL cells for 24 hours at 11°C. The short-range β-particles emitted by [3H]dTTP result in self-irradiation of labeled CHO cells; thus, biological effects on neighboring AL cells can be attributed to the bystander response. Nonlabeled bystander AL cells were isolated from among labeled CHO cells by using a magnetic separation technique. Treatment of CHO cells with 100 μCi [3H]dTTP resulted in a 14-fold increase in bystander mutation incidence among neighboring AL cells compared with controls. Multiplex PCR analysis revealed the types of mutants to be significantly different from those of spontaneous origin. The free radical scavenger DMSO or the gap junction inhibitor Lindane within the clusters significantly reduced the mutation incidence. The use of AL cells that are dominant negative for connexin 43 and lack gap junction formation produced a complete attenuation of the bystander mutagenic response. These data provide evidence that low LET radiation can induce bystander mutagenesis in a three-dimensional model and that reactive oxygen species and intercellular communication may have a modulating role. The results of this study will address the relevant issues of actual target size and radiation quality and are likely to have a significant effect on our current understanding of radiation risk assessment.
Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy
Authors: Michael R. Ehrenstein, Jamie G. Evans, Animesh Singh, Samantha Moore, Gary Warnes, David A. Isenberg, Claudia Mauri
Journal: The Journal of Experimental Medicine (2004)

Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
Celecoxib Up-Regulates the Expression of the ζ Chain of T Cell Receptor Complex in Tumor-Infiltrating Lymphocytes in Human Cervical Cancer
Authors: Gabriella Ferrandina, Franco Oreste Ranelletti, Francesco Legge, Vanda Salutari, Enrica Martinelli, Andrea Fattorossi, Domenica Lorusso, Gianfranco Zannoni, Valerio Vellone, Amelia Paglia, Giovanni Scambia
Journal: Clinical Cancer Research (2006)

Abstract Purpose: We evaluated the effects of celecoxib treatment on tumor-infiltrating lymphocyte (TIL) subsets [CD3+, CD4+,CD8+, CD25+, and T cell receptor (TCR)-ζ–expressing cells] and tryptase-positive mast cells in cervical tumors. Circulating levels of cytokines [interleukin (IL)-1β, IL-10, tumor necrosis factor-α, IL-6, and IL-12] and angiogenesis-modulating factors (vascular endothelial growth factor and endostatin) have also been analyzed. Experimental Design: Cervical tumor biopsies and blood samples were obtained at the time of diagnosis and after 10 days of celecoxib treatment (400 mg b.i.d., at 8:00 a.m. and 8:00 p.m.) in 27 cases. Immunohistochemistry and ELISA assays were used to assess the expression of biological factors in tumor tissue and circulating levels of cytokines and angiogenic molecules. Results: We showed a statistically significant increase in the percentage of TIL expressing the TCR-ζ chain after celecoxib treatment: indeed, in cases exposed to celecoxib, the percentage of TCR-ζ+ cells ranged from 5.0 to 50.0 (median, 22.5) with respect to baseline expression (range, 3.0-50.0; median, 10.0; P = 0.0016). There was no significant treatment-related difference in the percentage of CD3+, CD4+, CD8+, and CD25+ TIL as well as in tryptase-positive cells. IL-12 levels were significantly reduced in posttreatment samples with respect to baseline levels (P = 0.002). We also found a reduction in the circulating levels of vascular endothelial growth factor, and a statistically significant increase of serum endostatin levels (P = 0.035). Conclusions: We reported the first evidence in humans that celecoxib restores ζ expression by TIL in primary cervical tumors, suggesting that a positive modulation of immune function may serve as an additional mechanism supporting the antitumor effect of this class of drugs.
Backtracking? Rehearsing and replaying some old arguments about short-term memory
Authors: Rosaleen A. McCarthy, E. K. Warrington
Journal: Behavioral and Brain Sciences (1999)

We discuss the role of short-term auditory verbal storage within a working memory system. Data from single case studies of patients with left parietal lesions and selective impairment of memory span are discussed in order to address the question of the functions of short-term memory in language processing. The backup resource of auditory verbal short-term memory is required for those tasks that necessitate backtracking in order to integrate a verbal message within a developing central cognitive representation.
Type IV Collagen Induces Podocytic Features in Bone Marrow Stromal Stem Cells In Vitro
Authors: Julie Perry, Stephanie Tam, Keqin Zheng, Yoshikazu Sado, Howard Dobson, Barbara Jefferson, Robert Jacobs, Paul S. Thorner
Journal: Journal of the American Society of Nephrology (2005)

Bone marrow-derived stromal stem cells (BMSC) can differentiate along a variety of mesenchymal lines, including mesangial cells. For determining whether BMSC can be induced to differentiate along podocytic lines in vitro, canine BMSC were cultured on plastic, type I collagen, and NC1 hexamers of type IV collagen from normal and Alport canine glomerular basement membrane. Results were compared with a mouse podocyte cell line. In the case of the podocyte line, differentiation occurred on all three matrices as indicated by the expression of synaptopodin and CD2-associated protein (CD2AP) and organization of myosin heavy chain IIA into a linear pattern. BMSC proliferated equally well on all matrices, but cells that were grown on type IV collagen NC1 hexamers became larger and stellate. Evidence for podocytic differentiation occurred on all three collagen matrices as indicated by the redistribution of myosin IIA to a linear pattern and expression of synaptopodin, CD2AP, and alpha-actinin. A punctate distribution of CD2AP was seen only in cells that were grown on normal and Alport glomerular basement membrane NC1 hexamers. Differentiated podocytes expressed the alpha1, alpha2, and alpha5 chains of type IV collagen but at higher levels in cells that were grown on NC1 hexamers. Similar results were obtained in BMSC for the alpha1 and alpha2 chains only. The alpha3, alpha4, and alpha6 chains were never detected in the podocyte line or BMSC. These results indicate that BMSC undergo a degree of podocytic differentiation in vitro and greater when grown on type IV collagen NC1 hexamers than type I collagen. Alport and normal NC1 hexamers seem equally permissive to BMSC growth and differentiation, suggesting that these processes are not influenced specifically by the alpha3/alpha4/alpha5 network. BMSC may be useful in the development of stem cell-based reconstitution of glomeruli that are damaged by disease and for gene therapy of genetic glomerular diseases such as Alport syndrome.
Whole-genome sequencing and comprehensive variant analysis of a Japanese individual using massively parallel sequencing
Authors: Akihiro Fujimoto, Hidewaki Nakagawa, Naoya Hosono, Kaoru Nakano, Tetsuo Abe, Keith A Boroevich, Masao Nagasaki, Rui Yamaguchi, Tetsuo Shibuya, Michiaki Kubo, Satoru Miyano, Yusuke Nakamura, Tatsuhiko Tsunoda
Journal: Nature Genetics (2010)
Improved oxygen release: an adaptation of mature red cells to hypoxia
Authors: Miles J. Edwards, Miles J. Novy, Carrie-Lou Walters, James Metcalfe
Journal: Journal of Clinical Investigation (1968)

Blood from patients with erythrocytosis secondary to arterial hypoxemia due either to congenital heart disease or to chronic obstructive pulmonary disease was shown to have a decreased affinity for oxygen; the average oxygen pressure required to produce 50% saturation of hemoglobin with oxygen was 29.8 mm Hg (average normal, 26.3 mm Hg). Such a displacement of the blood oxygen equilibrium curve promotes the release of oxygen from blood to the tissues. Studies were also performed upon blood from a man with complete erythrocyte aplasia who received all of his red cells by transfusion from presumably normal persons. With mild anemia (hematocrit, 28%), the affinity of his blood for oxygen was slightly diminished (an oxygen pressure of 27.0 mm Hg was required to produce 50% saturation of hemoglobin with oxygen). With severe anemia (hematocrit, 13.5%), however, his blood had a markedly decreased oxygen affinity (an oxygen pressure of 29.6 mm Hg was required to produce 50% saturation of hemoglobin with oxygen). We conclude that patients with various conditions characterized by an impairment in the oxygen supply system to tissues respond with a diminished affinity of their blood for oxygen. Although the mechanism which brings about this adaptation is not known, the displacement of the oxygen equilibrium curve is associated with an increase in heme-heme interaction. The decrease in blood oxygen affinity need not occur during erythropoiesis, but may be imposed upon mature circulating red cells.
Randomized Phase III Trial Comparing Bexarotene (L1069-49)/Cisplatin/Vinorelbine With Cisplatin/Vinorelbine in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT I
Authors: Rodryg Ramlau, Petr Zatloukal, Jacek Jassem, Paul Schwarzenberger, Sergei V. Orlov, Maya Gottfried, Jose Rodrigues Pereira, Guillermo Temperley, Rosa Negro-Vilar, Samia Rahal, Joseph K. Zhang, Andres Negro-Vilar, Zofia E. Dziewanowska
Journal: Journal of Clinical Oncology (2008)

This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC).Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m(2)/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted.A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm).The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.
Early palliative care in non-small cell lung cancer improves quality of life and mood, and may result in longer survival
Authors: D. B. Land
Journal: Thorax (2011)

In this single-centre unblinded study performed in Massachusetts over 3 years, 151 outpatients with newly diagnosed metastatic non-small cell lung cancer and with a performance status of 0–2 were randomised to either standard oncological care alone or to standard care plus early palliative care.

The study groups were broadly similar and the results were analysed on an intention-to-treat basis at 12 weeks; 14% of patients in the …
Curability of Patients With Acute Myeloid Leukemia Who Did Not Undergo Transplantation in First Remission
Authors: Alan K. Burnett, Anthony Goldstone, Robert K. Hills, Donald Milligan, Archie Prentice, John Yin, Keith Wheatley, Ann Hunter, Nigel Russell
Journal: Journal of Clinical Oncology (2013)

The aims of this study were to quantify the prospects of salvage treatment of patients who did not undergo transplantation in first complete remission (CR1) and to assess the contribution of allograft in second complete remission (CR2) with respect to major risk groups. This evaluation can inform the decision whether to offer a transplant in CR1.Of 8,909 patients who entered the Medical Research Council AML10, AML12, and AML15 trials, 1,271 of 3,919 patients age 16 to 49 years who did not receive a transplant in CR1 relapsed. Of these patients, 19% are alive beyond 5 years compared with 7% of patients who relapsed after an allograft in CR1. Overall survival and the contribution of a transplant in CR2 were assessed overall and by cytogenetic risk group by using Mantel-Byar analysis.Fifty-five percent of patients who relapsed entered CR2. This percentage varied by risk group as follows: favorable (82%), intermediate (54%), adverse (27%), and unknown (53%), which resulted in 5-year survivals of 32%, 17%, 7%, and 23%, respectively. Sixty-seven percent of remitters received an allotransplant that delivered superior survival compared with patients who did not receive a stem-cell transplant (42% v 16%). A more-stringent assessment of a transplant by using delayed-entry (Mantel-Byar) analysis confirmed the benefit of transplant overall and within intermediate and adverse risk groups but not the favorable subgroup.Successful salvage treatment of patients who do not undergo transplantation in CR1 and relapse can be achieved in 19% of patients, which is improved by a transplant except in favorable risk disease. This result suggests that, for intermediate-risk patients in particular, equivalent overall survival can be achieved by delaying transplantation until after relapse, which would require many fewer transplants.