tbuckley/cabot-search huggingface dataset:
Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8+ T cells
Authors: Claudia Wrzesinski, Chrystal M. Paulos, Luca Gattinoni, Douglas C. Palmer, Andrew Kaiser, Zhiya Yu, Steven A. Rosenberg, Nicholas P. Restifo
Journal: Journal of Clinical Investigation (2007)

Depleting host immune elements with nonmyeloablative regimens prior to the adoptive transfer of tumor-specific CD8(+) T cells significantly enhances tumor treatment. In the current study, superior antitumor efficacy was achieved by further increasing the intensity of lymphodepletion to a level that required HSC transplantation. Surprisingly, the HSC transplant and not the increased lymphodepletion caused a robust expansion of adoptively transferred tumor-specific CD8(+) T cells. The HSC-driven cell expansion of effector, but not of naive, CD8(+) T cells was independent of in vivo restimulation by MHC class I-expressing APCs. Simultaneously, HSCs also facilitated the reconstitution of the host lymphoid compartment, including inhibitory elements, not merely via the production of progeny cells but by enhancing the expansion of cells that had survived lymphodepletion. Profound lymphodepletion, by myeloablation or by genetic means, focused the nonspecific HSC boost preferentially toward the transferred tumor-specific T cells, leading to successful tumor treatment. These findings indicate that CD8(+) T cell-mediated tumor responses can be efficiently driven by HSCs in the myeloablative setting and have substantial implications for the design of new antitumor immunotherapies.
Suppression of Urokinase Receptor Expression by Thalidomide Is Associated with Inhibition of Nuclear Factor κB Activation and Subsequently Suppressed Ovarian Cancer Dissemination
Authors: Hiroshi Kobayashi, Tatsuo Yagyu, Toshiharu Kondo, Noriyuki Kurita, Kiyokazu Inagaki, Shoji Haruta, Ryuji Kawaguchi, Takashi Kitanaka, Yoshiharu Sakamoto, Yoshihiko Yamada, Naohiro Kanayama, Toshihiko Terao
Journal: Cancer Research (2005)

Abstract Thalidomide has been used to treat a variety of diseases ranging from alleviation of autoimmune disorders to prevention of metastasis of cancers. It has been shown previously that increased levels of urokinase-type plasminogen activator receptor (uPAR) correlate well with higher invasive phenotype. We examined whether thalidomide is able to suppress the expression of uPAR mRNA and protein in human ovarian cancer cell line HRA and human chondrosarcoma cell line HCS-2/8. Here, we show that: (a) thalidomide suppresses the expression of constitutive and transforming growth factor-β1 (TGF-β1)–induced uPAR mRNA and protein; (b) a nuclear factor κB (NF-κB) activation system (phosphorylation of IκB-α and degradation of IκB-α) is necessary for the TGF-β1-induced increase in uPAR expression, because l-1-tosylamido-2-phenylethyl chloromethyl ketone, a NF-κB inhibitor, reduced the uPAR production as well as mRNA expression; (c) thalidomide failed to further strengthen l-1-tosylamido-2-phenylethyl chloromethyl ketone's action; (d) the once-daily i.p. administration of thalidomide (400 μg/g body weight/d) decreased progressive growth of HRA tumors and ascites formation in an in vivo animal model; and (e) the once-daily i.p. administration of thalidomide in combination with paclitaxel (i.p., 100 μg/20 g at days 2 and 5) significantly decreased progressive growth of HRA cells in a synergistic fashion. We conclude that thalidomide down-regulates constitutive and TGF-β1-stimulated uPAR mRNA and protein expression possibly through suppression of NF-κB activation. Furthermore, combination therapy with thalidomide plus paclitaxel may be an effective way to markedly reduce i.p. tumor growth and ascites in ovarian cancer dissemination.
A Global Expression-based Analysis of the Consequences of the t(4;14) Translocation in Myeloma
Authors: Ann M. Dring, Faith E. Davies, James A. L. Fenton, Philippa L. Roddam, Kathryn Scott, David Gonzalez, Sara Rollinson, Andrew C. Rawstron, Karen S. Rees-Unwin, Cheng Li, Nikhil C. Munshi, Kenneth C. Anderson, Gareth J. Morgan
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Our purpose in this report was to define genes and pathways dysregulated as a consequence of the t(4;14) in myeloma, and to gain insight into the downstream functional effects that may explain the different prognosis of this subgroup. Experimental Design: Fibroblast growth factor receptor 3 (FGFR3) overexpression, the presence of immunoglobulin heavy chain-multiple myeloma SET domain (IgH-MMSET) fusion products and the identification of t(4;14) breakpoints were determined in a series of myeloma cases. Differentially expressed genes were identified between cases with (n = 5) and without (n = 24) a t(4;14) by using global gene expression analysis. Results: Cases with a t(4;14) have a distinct expression pattern compared with other cases of myeloma. A total of 127 genes were identified as being differentially expressed including MMSET and cyclin D2, which have been previously reported as being associated with this translocation. Other important functional classes of genes include cell signaling, apoptosis and related genes, oncogenes, chromatin structure, and DNA repair genes. Interestingly, 25% of myeloma cases lacking evidence of this translocation had up-regulation of the MMSET transcript to the same level as cases with a translocation. Conclusions: t(4;14) cases form a distinct subgroup of myeloma cases with a unique gene signature that may account for their poor prognosis. A number of non-t(4;14) cases also express MMSET consistent with this gene playing a role in myeloma pathogenesis.
A rate-independent technique for analysis of nucleic acid sequences: evolutionary parsimony.
Authors: J A Lake
Journal: Molecular Biology and Evolution (1987)

The method of evolutionary parsimony--or operator invariants--is a technique of nucleic acid sequence analysis related to parsimony analysis and explicitly designed for determining evolutionary relationships among four distantly related taxa. The method is independent of substitution rates because it is derived from consideration of the group properties of substitution operators rather than from an analysis of the probabilities of substitution in branches of a tree. In both parsimony and evolutionary parsimony, three patterns of nucleotide substitution are associated one-to-one with the three topologically linked trees for four taxa. In evolutionary parsimony, the three quantities are operator invariants. These invariants are the remnants of substitutions that have occurred in the interior branch of the tree and are analogous to the substitutions assigned to the central branch by parsimony. The two invariants associated with the incorrect trees must equal zero (statistically), whereas only the correct tree can have a nonzero invariant. The chi 2-test is used to ascertain the nonzero invariant and the statistically favored tree. Examples, obtained using data calculated with evolutionary rates and branchings designed to camouflage the true tree, show that the method accurately predicts the tree, even when substitution rates differ greatly in neighboring peripheral branches (conditions under which parsimony will consistently fail). As the number of substitutions in peripheral branches becomes fewer, the parsimony and the evolutionary-parsimony solutions converge. The method is robust and easy to use.
Simultaneous Autologous Transplantation of Cocultured Mesenchymal Stem Cells and Skeletal Myoblasts Improves Ventricular Function in a Murine Model of Chagas Disease
Authors: L.C. Guarita-Souza, K.A.T. Carvalho, V. Woitowicz, C. Rebelatto, A. Senegaglia, P. Hansen, N. Miyague, J.C. Francisco, M. Olandoski, J.R. Faria-Neto, P. Brofman
Journal: Circulation (2006)

Background— Cellular transplantation is emerging as a promising strategy for the treatment of postinfarction ventricular dysfunction. Whether its beneficial effects can be extended to other cardiomyopathies remains an unexplored question. We evaluated the histological and functional effects of simultaneous autologous transplantation of co-cultured stem cells and skeletal myoblasts in an experimental model of dilated cardiomyopathy caused by Chagas disease, characterized by diffuse fibrosis and impairment of microcirculation. Methods and Results— Wistar rats weighing 200 grams were infected intraperitoneally with 15×10 4 trypomastigotes. After 8 months, 2-dimensional echocardiographic study was performed for baseline assessment of left ventricle (LV) ejection fraction (EF) (%), left ventricle end-diastolic volume (LVEDV) (mL), and left ventricle end-systolic volume (LVESV) (mL). Animals with LV dysfunction (EF &lt;37%) were selected for the study. Autologous skeletal myoblasts were isolated from muscle biopsy and mesenchymal stem cells from bone marrow aspirates were co-cultured in vitro for 14 days, yielding a cell viability of &gt;90%. Eleven animals received autologous transplant of 5.4×10 6 ±8.0×10 6 cells (300 μL) into the LV wall. The control group (n=10) received culture medium (300 μL). Cell types were identified with vimentin and fast myosin. After 4 weeks, ventricular function was reassessed by echo. For histological analysis, heart tissue was stained with hematoxylin and eosin and immunostained for fast myosin. After 4 weeks, cell transplantation significantly improved EF and reduced LVEDV and LVESV. No change was observed in the control group. Conclusion— The co-transplant of stem cells and skeletal myoblasts is functionally effective in the Chagas disease ventricular dysfunction.
Importance of Myeloid Dendritic Cells in Persistent Airway Disease after Repeated Allergen Exposure
Authors: Toshiyuki Koya, Taku Kodama, Katsuyuki Takeda, Nobuaki Miyahara, Eun-Seok Yang, Christian Taube, Anthony Joetham, Jung-Won Park, Azzeddine Dakhama, Erwin W. Gelfand
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice.Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or 11 occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors.Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta(1), eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5, and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrow-derived dendritic cells restored AHR and airway eosinophilia.These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.
Occupational asthma due to oil mists.
Authors: A S Robertson, D C Weir, P S Burge
Journal: Thorax (1988)

Twenty five patients who were exposed to oil mists at their place of work were investigated for possible work related asthma. Serial peak expiratory flow recordings showed 13 to have definite work related asthma, seven equivocal work related asthma, and three asthma unrelated to work; two had normal recordings. Subjects with work related asthma often produced different patterns of peak flow response during the working week; patterns also varied between patients. Six of these patients had bronchial tests with oil from their place of work. Three had asthma induced by exposure to unused (clean) soluble oil and one reacted to used but not to clean oil. The challenge tests in the remaining two gave inconclusive results. It is concluded that occupational asthma due to oil mists is common, the peak flow response is heterogeneous, and the provoking agent within the oil may vary from worker to worker.
Cost-optimisation of screening for latent tuberculosis in close contacts
Authors: R. Diel
Journal: European Respiratory Journal (2006)

The aim of the present study was to perform cost-minimisation analysis of contact investigation from a public health perspective using the tuberculin skin test (TST) and a new blood assay, QuantiFERON-TB Gold (QFT-G). A decision-analysis model simulated the costs of investigating a cohort of adult close tuberculosis contacts by the public health service following the current German guidelines over a period of 2 yrs. The economic outcomes were compared with alternative screening strategies. These were: 1) QFT-G instead of TST; 2) TST followed by QFT-G; and 3) TST followed by QFT-G in vaccinated (bacille Calmette-Guérin (BCG)) subjects. In a base-case analysis, the costs of TST-based screening were 91.06 Euros (EUR).contact(-1), assuming a 1% tuberculosis-case-finding incidence. The least expensive strategy was TST screening plus subsequent QFT-G testing (52.05 EUR), resulting in a 43% cost reduction. Using QFT-G alone in BCG-vaccinated subjects who tested positive in the TST led to a 39% cost reduction. The savings using QFT-G alone instead of TST amounted to 29.77 EUR.contact(-1). The results depended on the acquisition costs assumed and the proportion of positive results in TST-based screening. Screening for tuberculosis by combining tuberculin skin testing and QuantiFERON-TB Gold markedly reduces public health costs compared with tuberculin skin test screening alone.
Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial
Authors: Leonard A Mattano, Meenakshi Devidas, James B Nachman, Harland N Sather, Stephen P Hunger, Peter G Steinherz, Paul S Gaynon, Nita L Seibel
Journal: The Lancet Oncology (2012)
Charity makes cancer gene freely available across Europe
Authors: Susan Mayor
Journal: BMJ (2004)

The charity Cancer Research UK announced last week that it had obtained a Europe-wide patent onthe hereditary breast cancer gene BRCA2 and will allow publicly owned laboratories and hospitals to use the gene free of charge.

The granting of the European patent will extend access to the gene. Currently access is available to UK researchers because the charity already holds a UK patent on the gene.

The patent covers all attempts to sequence the gene or to test for damaged or inactive variants—such as testing people for BRCA2 variants to assess their risk of …
Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment
Authors: Xueru Mu, Regina Español-Suñer, Ingmar Mederacke, Silvia Affò, Rita Manco, Christine Sempoux, Frédéric P. Lemaigre, Arlind Adili, Detian Yuan, Achim Weber, Kristian Unger, Mathias Heikenwälder, Isabelle A. Leclercq, Robert F. Schwabe
Journal: Journal of Clinical Investigation (2015)

In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19–, A6- and α-fetoprotein–positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.
Characterizing the Native Codon Usages of a Genome: An Axis Projection Approach
Authors: J. J. Davis, G. J. Olsen
Journal: Molecular Biology and Evolution (2010)

Codon usage can provide insights into the nature of the genes in a genome. Genes that are "native" to a genome (have not been recently acquired by horizontal transfer) range in codon usage from a low-bias "typical" usage to a more biased "high-expression" usage characteristic of genes encoding abundant proteins. Genes that differ from these native codon usages are candidates for foreign genes that have been recently acquired by horizontal gene transfer. In this study, we present a method for characterizing the codon usages of native genes—both typical and highly expressed—within a genome. Each gene is evaluated relative to a half line (or axis) in a 59D space of codon usage. The axis begins at the modal codon usage, the usage that matches the largest number of genes in the genome, and it passes through a point representing the codon usage of a set of genes with expression-related bias. A gene whose codon usage matches (does not significantly differ from) a point on this axis is a candidate native gene, and the location of its projection onto the axis provides a general estimate of its expression level. A gene that differs significantly from all points on the axis is a candidate foreign gene. This automated approach offers significant improvements over existing methods. We illustrate this by analyzing the genomes of Pseudomonas aeruginosa PAO1 and Bacillus anthracis A0248, which can be difficult to analyze with commonly used methods due to their biased base compositions. Finally, we use this approach to measure the proportion of candidate foreign genes in 923 bacterial and archaeal genomes. The organisms with the most homogeneous genomes (containing the fewest candidate foreign genes) are mostly endosymbionts and parasites, though with exceptions that include Pelagibacter ubique and Beutenbergia cavernae. The organisms with the most heterogeneous genomes (containing the most candidate foreign genes) include members of the genera Bacteroides, Corynebacterium, Desulfotalea, Neisseria, Xylella, and Thermobaculum.
Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction
Authors: Lin Sun, Ping Xie, Jun Wada, Naoki Kashihara, Fu-you Liu, Yanan Zhao, Deepak Kumar, Sumant S. Chugh, Farhad R. Danesh, Yashpal S. Kanwar
Journal: Journal of the American Society of Nephrology (2008)

The role of tubular injury in diabetic nephropathy is relatively unknown, despite that apoptosis of tubular epithelial cells is commonly observed in human renal biopsies. The GTPase Ras-proximate-1 (Rap1b) is upregulated in the hyperglycemic state and is known to increase B-Raf, an antiapoptotic effector protein. In this study, the effects of high glucose on renal tubular apoptosis and the potential ability for Rap1b to ameliorate these effects were investigated. In the kidneys of diabetic mice, apoptotic tubular cells and dysmorphic mitochondria were observed, Bcl-2 expression was decreased, and Bax expression was increased. Total Rap1b expression was slightly increased, but its associated GTPase activity was significantly decreased. In vitro, high extracellular glucose led to decreased Bcl-2 expression, reduced Rap1b GTPase activity, and increased levels of both Bax and GTPase activating protein in a proximal tubular cell line (HK-2). These changes were accompanied by increased DNA fragmentation, decreased high molecular weight mitochondrial DNA, altered mitochondrial morphology and function, disrupted Bcl-2–Bax and Bcl-2–Rap1b interactions, and reduced cell survival. Overexpression of Rap1b partially prevents these abnormalities. Furthermore, the BH4 domain of Bcl-2 was found to be required for successful protein–protein interaction between Bcl-2 and Rap1b. In summary, these data suggest that Rap1b ameliorates glucose-induced mitochondrial dysfunction in renal tubular cells.
Predictive Factors for Interstitial Lung Disease, Antitumor Response, and Survival in Non–Small-Cell Lung Cancer Patients Treated With Gefitinib
Authors: Masahiko Ando, Isamu Okamoto, Nobuyuki Yamamoto, Koji Takeda, Kenji Tamura, Takashi Seto, Yutaka Ariyoshi, Masahiro Fukuoka
Journal: Journal of Clinical Oncology (2006)

Interstitial lung disease (ILD) is a serious adverse effect of gefitinib, but its prevalence and risk factors remain largely unknown. We examined the prevalence of and risk factors for gefitinib-induced ILD associated with practical use of the drug in Japanese with non-small-cell lung cancer (NSCLC).Clinical information was retrospectively assembled for NSCLC patients who started gefitinib treatment at affiliated institutions of the West Japan Thoracic Oncology Group between August 31 and December 31, 2002. Medical records of patients who developed pulmonary infiltrates were reviewed by a central committee of extramural experts for identification of patients with gefitinib-induced ILD. Multivariate logistic or Cox regression analysis was performed to identify independent predictive factors for ILD, antitumor response, and survival.Seventy cases of and 31 deaths from gefitinib-induced ILD were identified among 1,976 consecutively treated patients at 84 institutions, corresponding to a prevalence of 3.5% and mortality of 1.6%. Gefitinib-induced ILD was significantly associated with male sex, a history of smoking, and coincidence of interstitial pneumonia (odds ratios = 3.10, 4.79, and 2.89, respectively). Predictive factors for response were female sex, no history of smoking, adenocarcinoma histology, metastatic disease, and good performance status (PS), whereas predictive factors for survival were female sex, no history of smoking, adenocarcinoma histology, nonmetastatic disease, good PS, and previous chest surgery.ILD is a serious adverse effect of gefitinib in the clinical setting that cannot be ignored. However, patient selection based on sex and smoking history can minimize ILD risk and maximize the clinical benefit of gefitinib.
Provision of physiotherapy at the Tsing Ma Bridge international marathon and 10 km race in Hong Kong.
Authors: S S Yeung, E W Yeung, T W Wong
Journal: British Journal of Sports Medicine (1998)

This report examines the delivery of sports physiotherapy at the Tsing Ma Bridge marathon and 10 km race in Hong Kong. The incidence, type of injury encountered, and treatment modalities selected are examined. The report also highlights the flexibility required when planning the provision of such a service.