tbuckley/cabot-search huggingface dataset:
Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer
Authors: M L G Janssen-Heijnen
Journal: Thorax (2004)

With the rising mean age, more patients will be diagnosed with one or more other serious diseases at the time of lung cancer diagnosis. Little is known about the best way to treat elderly patients with comorbidity or the outcome of treatment. This study was undertaken to evaluate the independent effects of age and comorbidity on treatment and prognosis in patients with non-small cell lung cancer (NSCLC).All patients with NSCLC diagnosed between 1995 and 1999 in the southern part of the Netherlands (n = 4072) were included.The proportion of patients with localised NSCLC who underwent surgery was 92% in patients younger than 60 years and 9% in those aged 80 years or older. In patients aged 60-79 years this proportion also decreased with comorbidity. In patients with non-localised NSCLC the proportion receiving chemotherapy was considerably higher for those aged less than 60 years (24%) than in those aged 80 or older (2%). The number of comorbid conditions had no significant influence on the treatment chosen for patients with non-localised disease. Multivariable survival analyses showed that age, tumour size, and treatment were independent prognostic factors for patients with localised disease, and stage of disease and treatment for those with non-localised disease. Comorbidity had no independent prognostic effect.It is questionable whether the less aggressive treatment of elderly patients with NSCLC is justified.
Human Telomerase Reverse Transcriptase-Transduced Human Cytotoxic T Cells Suppress the Growth of Human Melanoma in Immunodeficient Mice
Authors: Natascha C. V. Verra, Annelies Jorritsma, Kees Weijer, Janneke J. Ruizendaal, Arie Voordouw, Pauline Weder, Erik Hooijberg, Ton N. M. Schumacher, John B. A. G. Haanen, Hergen Spits, Rosalie M. Luiten
Journal: Cancer Research (2004)

Abstract Immunotherapy of melanoma by adoptive transfer of tumor-reactive T lymphocytes aims at increasing the number of activated effectors at the tumor site that can mediate tumor regression. The limited life span of human T lymphocytes, however, hampers obtaining sufficient cells for adoptive transfer therapy. We have shown previously that the life span of human T cells can be greatly extended by transduction with the human telomerase reverse transcriptase (hTERT) gene, without altering antigen specificity or effector function. We developed a murine model to evaluate the efficacy of hTERT-transduced human CTLs with antitumor reactivity to eradicate autologous tumor cells in vivo. We transplanted the human melanoma cell line melAKR or melAKR-Flu, transduced with a retrovirus encoding the influenza virus/HLA-A2 epitope, in RAG-2−/− IL-2Rγ −/− double knockout mice. Adoptive transfer of the hTERT-transduced influenza virus-specific CTL clone INFA24 or clone INFA13 inhibited the growth of melAKR-Flu tumors in vivo and not of the parental melAKR melanoma cells. Furthermore, the hTERT-transduced CTL clone INFA13 inhibited tumor growth to the same extent in vivo as the untransduced CTL clone, as determined by in vivo imaging of luciferase gene-transduced melAKR-Flu tumors, indicating that hTERT did not affect the in vivo function of CTL. These results demonstrate that hTERT-transduced human CTLs are capable of mediating antitumor activity in vivo in an antigen-specific manner. hTERT-transduced MART-1-specific CTL clones AKR4D8 and AKR103 inhibited the growth of syngeneic melAKR tumors in vivo. Strikingly, melAKR-Flu cells were equally killed by the MART-1-specific CTL clones and influenza virus-specific CTL clones in vitro, but only influenza-specific CTLs were able to mediate tumor regression in vivo. The influenza-specific CTL clones were found to produce higher levels of IFNγ on tumor cell recognition than the MART-1-specific CTL clones, which may result from the higher functional avidity of the influenza virus-specific CTL clones. Also, melAKR-Flu tumors were growing faster than melAKR tumors, which may have surpassed the relatively modest antitumor effect of the MART-1-specific CTL, as compared with the influenza virus-specific CTL. Taken together, the adoptive transfer model described here shows that hTERT-transduced T cells are functional in vivo, and allows us to evaluate the balance between functional activity of the CTL and tumor growth rate in vivo, which determines the efficacy of CTLs to eradicate tumors in adoptive transfer therapy.
Lethal myelofibrosis induced by <i>Bmi1</i>-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes
Authors: Hideyuki Oguro, Jin Yuan, Satomi Tanaka, Satoru Miyagi, Makiko Mochizuki-Kashio, Hitoshi Ichikawa, Satoshi Yamazaki, Haruhiko Koseki, Hiromitsu Nakauchi, Atsushi Iwama
Journal: The Journal of Experimental Medicine (2012)

Polycomb-group (PcG) proteins form the multiprotein polycomb repressive complexes (PRC) 1 and 2, and function as transcriptional repressors through histone modifications. They maintain the proliferative capacity of hematopoietic stem and progenitor cells by repressing the transcription of tumor suppressor genes, namely Ink4a and Arf, and thus have been characterized as oncogenes. However, the identification of inactivating mutations in the PcG gene, EZH2, unveiled a tumor suppressor function in myeloid malignancies, including primary myelofibrosis (PMF). Here, we show that loss of another PcG gene, Bmi1, causes pathological hematopoiesis similar to PMF. In a mouse model, loss of Bmi1 in Ink4a-Arf−/− hematopoietic cells induced abnormal megakaryocytopoiesis accompanied by marked extramedullary hematopoiesis, which eventually resulted in lethal myelofibrosis. Absence of Bmi1 caused derepression of a cohort of genes, including Hmga2, which is an oncogene overexpressed in PMF. Chromatin immunoprecipitation assays revealed that Bmi1 directly represses the transcription of Hmga2. Overexpression of Hmga2 in hematopoietic stem cells induced a myeloproliferative state with enhanced megakaryocytopoiesis in mice, implicating Hmga2 in the development of pathological hematopoiesis in the absence of Bmi1. Our findings provide the first genetic evidence of a tumor suppressor function of Bmi1 and uncover the role of PcG proteins in restricting growth by silencing oncogenes.
Absence of the t(14;18) chromosomal translocation in primary cutaneous B-cell lymphoma
Authors: F.J. Child, R. Russell-Jones, A.J. Woolford, E. Calonje, A. Photiou, G. Orchard, S.J. Whittaker
Journal: British Journal of Dermatology (2001)

Background The t(14;18)(q32;q21) chromosomal translocation is found in the majority of nodal follicular lymphomas and in a lower percentage of systemic high‐grade diffuse large B‐cell lymphomas. The translocation results in the juxtaposition of the bcl‐2 gene on chromosome 18 with the immunoglobulin heavy chain joining region on chromosome 14. Bcl‐2 protein prevents apoptosis and the translocation leads to overexpression of a functionally normal Bcl‐2 protein that prevents apoptosis of neoplastic cells. Objectives The purpose of our study was to analyse cases of primary cutaneous B‐cell lymphoma (PCBCL) for the presence of the t(14;18) translocation and to correlate the results with Bcl‐2 expression and histological subtype. Methods Forty‐four cutaneous B‐cell lymphoid proliferations (36 PCBCL, four follicular B‐cell lymphomas with cutaneous presentation and four reactive B‐cell infiltrates) were analysed by polymerase chain reaction amplification and polyacrylamide gel electrophoresis using consensus primers for the joining region on the immunoglobulin heavy chain gene in combination with either a primer for the major breakpoint region (MBR) or the minor cluster region (mcr) on chromosome 18. Results None of 36 PCBCL analysed demonstrated a t(14;18) translocation; however, three of four systemic follicular B‐cell lymphomas presenting in the skin were found to have a translocation in the MBR, which was confirmed by sequence analysis. Correlation with Bcl‐2 immunostaining showed that of seven patients with high‐grade cutaneous diffuse large B‐cell lymphoma, four were Bcl‐2 positive but had no evidence of a t(14;18) translocation. In the five cases classified as primary cutaneous follicle centre cell lymphoma, the neoplastic cells within the germinal centres failed to express Bcl‐2. However, Bcl‐2‐positive neoplastic cells were present in all four cases of systemic follicular lymphoma, including the case that did not show a t(14;18) translocation. In all cases of marginal zone lymphoma the marginal zone lymphocytes were Bcl‐2 positive. Conclusions These findings indicate that the t(14;18) translocation does not occur in PCBCL, which suggests the involvement of different pathogenetic mechanisms compared with their nodal counterparts. Furthermore, the detection of a t(14;18) translocation in cutaneous B‐cell lymphoma should suggest the presence of systemic disease, which underlies the need for exhaustive staging procedures.
Attentional Stimulus Selection through Selective Synchronization between Monkey Visual Areas
Authors: Conrado A. Bosman, Jan-Mathijs Schoffelen, Nicolas Brunet, Robert Oostenveld, Andre M. Bastos, Thilo Womelsdorf, Birthe Rubehn, Thomas Stieglitz, Peter De Weerd, Pascal Fries
Journal: Neuron (2012)
Angiotensin II receptor subtype AT1 and AT2 expression after heart transplantation
Authors: L Gullestad
Journal: Cardiovascular Research (1998)

Objective: Cardiac hypertrophy appears early after heart transplantation, and may represent a myocardial response to injury. Recent evidence suggests that angiotensin II (Ang II) may promote growth through the AT1 and inhibit growth through the AT2 receptor subtypes. We therefore asked whether hypertrophy after heart transplantation is characterized by alterations in Ang II receptor gene expression. Methods: The expression of Ang II receptor subtypes, AT1 and AT2, was analyzed in right ventricular endomyocardial biopsies taken from 10 human donor hearts prior to implantation (controls) and from 17 heart transplant recipients, 11 studied during annual evaluation (>1 year after transplantation) and 6 one week after transplantation. Competitive reverse transcription polymerase chain reaction (RT-PCR) was performed using synthetic RNA internal standards for both receptor subtypes. Results: AT1 and AT2 receptor mRNAs were detected in all samples. AT1 receptor mRNA decreased 4.5 fold (p<0.01) and AT2 receptor mRNA 4.2 fold (p<0.001) in transplant patients compared with controls. In the subgroup of patients examined one week after surgery AT1 was reduced relative to AT2 receptor mRNA, resulting in an altered ratio of AT1 to AT2 early after transplantation. There was no correlation between Ang II receptor levels and left ventricular wall thickness, and the decrease in receptor level did not correlate with any hemodynamic parameters, cyclosporine blood levels, or plasma renin, Ang II or pANP, except for a negative correlation between AT2 mRNA and plasma renin (r=−0.49,p=0.05). Conclusions: Contrary to our expectations, mRNA for both Ang II receptors was downregulated after heart transplantation. The cause of myocardial hypertrophy after heart transplantation is still unclear, but the hypertrophy does not appear to be driven by increased transcription of the AT1 receptor.
Greatly reduced lymphoproliferation in lpr mice lacking major histocompatibility complex class I.
Authors: M A Maldonado, R A Eisenberg, E Roper, P L Cohen, B L Kotzin
Journal: The Journal of Experimental Medicine (1995)

Mice homozygous for the lpr gene have a defect in fas (CD95), a cell surface receptor that belongs to the tumor necrosis factor receptor family and that mediates apoptosis. This genetic abnormality results in lymphoproliferation characterized by the accumulation of CD4-CD8- (double negative [DN]) T cells, autoantibody production, and background strain-dependent, end-organ disease. Our previous results suggested that major histocompatibility complex (MHC) class I may be involved in the development of DN cells. To test this hypothesis, we derived C57BL/6-lpr/lpr (B6/lpr) mice that were deficient for the beta 2-microglobulin gene (beta 2m lpr) and had no detectable class I expression. At 6 mo of age, compared with B6/lpr littermates with normal class I genes, these mice showed greatly reduced lymphadenopathy, mostly due to a dramatic decrease in the number of DN cells. Significant changes in the percentage of other T cell subsets were noted, but only gamma/delta+ T cells showed a marked increase in both percentage and absolute numbers. Analysis of T cell receptor V beta expression of the remaining DN T cells in beta 2m -lpr mice showed a shift to a CD4-like repertoire from a CD8-like repertoire in control B6/lpr mice, indicating that a small MHC class II selected DN population was unmasked in lpr mice lacking class I. We also found that the production of immunoglobulin G (IgG) autoantibodies (antichromatin and anti-single stranded DNA), total IgG and IgG2a, but not total IgM or IgM rheumatoid factor, was significantly reduced in the beta 2m -lpr mice. This work suggests that &amp;gt;90% of DN T cells in lpr mice are derived from the CD8 lineage and are selected on class I. However, a T cell subset selected on class II and T cells expressing gamma/delta are also affected by the lpr defect and become minor components of the aberrant DN population.
Mitochondrial Mutations Are a Late Event in the Progression of Head and Neck Squamous Cell Cancer
Authors: Suhail K. Mithani, Janis M. Taube, Shaoyu Zhou, Ian M. Smith, Wayne M. Koch, William H. Westra, Joseph A. Califano
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To determine the timing of mitochondrial mutations in the progression of head and neck squamous cell carcinoma. Experimental Design: Twenty-three mitochondrial mutations were identified in 12 tumors using a high-throughput mitochondrial sequencing array. Areas of adjacent dysplastic and normal epithelium adjacent to tumors were sequenced using conventional methods for the presence of mutations that occurred in the corresponding tumor. Results: Two of 23 (8.7%) tumor mitochondrial mutations (2 of 12 tumors) were present in both the areas of adjacent dysplasia and normal epithelium. Five of 23 (21.7%) tumor mitochondrial mutations (4 of 12 tumors) were present in areas of adjacent dysplasia. Eleven of 12 tumors contained nonsynonymous mutations that resulted in protein coding alterations. A significant difference (P &amp;lt; 0.01, χ2) was found in the incidence of mitochondrial mutation that occurred after development of cancer compared with adjacent areas dysplasia and normal epithelium. Conclusions: The majority of mitochondrial mutations occur during or after the transition of preneoplastic epithelium to cancer in head and neck squamous cell carcinoma, indicating that these are a late event in head and neck carcinogenesis.
Physiological consequence of lower vs upper lobe lung volume reduction in patients with advanced emphysema
Authors: Edward Ingenito, Larry Tsai
Journal: European Respiratory Journal (2011)

Objective(s):  Lower lobe lung volume reduction in patients with advanced emphysema is associated with less benefit that upper lobe therapy. We present computer modeling results that explain these observations, and can help direct treatment site selection in patients undergoing lung volume reduction therapy.   Methods:  The model considers alveoli as discrete units with an exponential pressure-volume relationship of the form (V(P tp ) = Vmax – Ae -kPtp ). Gravitational effects on transpulmonary pressure (Ptp), the extent of tissue destruction, airway closure effects, and extent of heterogeneity were incorporated as independent variables for predicting RV and RV/TLC.   Results:  Gravitational effects on Ptp are the major determinant of regional RV and overall RV/TLC. In upper lobe heterogeneous emphysema, changes in Ptp from volume reduction distend the remaining alveoli at end exhalation. However, RV and RV/TLC are reduced due to a decrease in the total number of diseased alveoli following treatment. In lower lobe heterogeneous emphysema, volume reduction distends already stretched upper lobe alveoli attenuating treatment effects on gas trapping. This phenomenon was more pronounced in homogeneous disease. Potential benefits of lower lobe volume reduction could be completely negated by upper lobe alveolar distention, resulting in no improvement, or even worsening of RV and RV/TLC despite alveolar resection.   Conclusions:  Gravitational effects largely explain why lower lobe volume reduction therapy is less therapeutic than upper lobe therapy. In patients with homogeneous emphysema, lower lobe therapy can actual worsen gas trapping despite resection of diseased tissue.
Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis
Authors: Jean Bourhis, Jens Overgaard, Hélène Audry, Kian K Ang, Michele Saunders, Jacques Bernier, Jean-Claude Horiot, Aurélie Le Maître, Thomas F Pajak, Michael G Poulsen, Brian O'Sullivan, Werner Dobrowsky, Andrzej Hliniak, Krzysztof Skladowski, John H Hay, Luiz HJ Pinto, Carlo Fallai, Karen K Fu, Richard Sylvester, Jean-Pierre Pignon
Journal: The Lancet (2006)
Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy
Authors: Steven L. Highfill, Yongzhi Cui, Amber J. Giles, Jillian P. Smith, Hua Zhang, Elizabeth Morse, Rosandra N. Kaplan, Crystal L. Mackall
Journal: Science Translational Medicine (2014)

Preventing trafficking of myeloid-derived suppressor cells to the tumor site enhances the efficiency of checkpoint blockade.
Long-term exposure to air pollution and asthma hospitalisations in older adults: a cohort study
Authors: Zorana Jovanovic Andersen, Klaus Bønnelykke, Martin Hvidberg, Steen S Jensen, Matthias Ketzel, Steffen Loft, Mette Sørensen, Anne Tjønneland, Kim Overvad, Ole Raaschou-Nielsen
Journal: Thorax (2011)

<h3>Background</h3> Exposure to air pollution in early life contributes to the burden of childhood asthma, but it is not clear whether long-term exposure to air pollution can lead to asthma onset or progression in adulthood. <h3>Objectives</h3> The authors studied the effect of exposure to traffic-related air pollution over 35 years on the risk for asthma hospitalisation in older people. <h3>Methods</h3> 57 053 participants in the Danish Diet, Cancer and Health cohort, aged 50–65 years at baseline (1993–1997), were followed up for first hospital admission for asthma until 2006, and the annual nitrogen dioxide (NO<sub>2</sub>) levels were estimated as a proxy of the exposure to traffic-related air pollution at the residential addresses of the participants since 1971. The association between NO<sub>2</sub> and hospitalisation for asthma was modelled using Cox regression, for the full cohort and in people with and without previous hospitalisations for asthma, and the effect modification by comorbid conditions was assessed. <h3>Results</h3> During 10.2 years9 median follow-up, 977 (1.9%) of 53 695 eligible people were admitted to hospital for asthma: 821 were first-ever admissions and 176 were readmissions. NO<sub>2</sub> levels were associated with risk for asthma hospitalisation in the full cohort (HR and 95% CI per IQR, 5.8 μg/m<sup>3</sup>: 1.12; 1.04–1.22), and for first-ever admissions (1.10; 1.01–1.20), with the highest risk in people with a history of asthma (1.41; 1.15–2.07) or chronic obstructive pulmonary disease (COPD) (1.30; 1.07–1.52) hospitalisation. <h3>Conclusions</h3> Long-term exposure to traffic-related air pollution increases the risk for asthma hospitalisation in older people. People with previous asthma or COPD hospitalisations are most susceptible.
Efficacy and Safety of AMG 853 in Asthma: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled Study
Authors: W.W. Busse, S.E. Wenzel, E.O. Meltzer, E.M. Kerwin, M.C. Liu, N. Zhang, Y. Chon, J. Lin, S. Lin
Journal: Journal of Allergy and Clinical Immunology (2012)
Study explores internet as a tool for care of diabetic patients
Authors: S. Gottlieb
Journal: BMJ (2000)

A new study involving patients with diabetes in the United States will show doctors whether it can be beneficial and affordable to use the internet to make high tech house calls.

Upstate Medical Center in Syracuse, New York, and Columbia University in New York City will use a $28m (£17.5m) federal grant to deliver health care through the internet into the homes of 750 rural and inner city diabetic patients over the next four years.

The grant from the US Health Care Financing Administration will provide patients with free personal computers with programming based on Microsoft Windows, internet access, and health monitoring equipment.

The study will recruit …
Stretch-induced programmed myocyte cell death.
Authors: W Cheng, B Li, J Kajstura, P Li, M S Wolin, E H Sonnenblick, T H Hintze, G Olivetti, P Anversa
Journal: Journal of Clinical Investigation (1995)

To determine the effects of loading on active and passive tensions, programmed cell death, superoxide anion formation, the expression of Fas on myocytes, and side-to-side slippage of myocytes, papillary muscles were exposed to 7-8 and 50 mN/mm2 and these parameters were measured over a 3-h period. Overstretching produced a 21- and a 2.4-fold increase in apoptotic myocyte and nonmyocyte cell death, respectively. Concurrently, the generation of reactive oxygen species increased 2.4-fold and the number of myocytes labeled by Fas protein 21-fold. Moreover, a 15% decrease in the number of myocytes included in the thickness of the papillary muscle was found in combination with a 7% decrease in sarcomere length and the inability of muscles to maintain stable levels of passive and active tensions. The addition of the NO-releasing drug, C87-3754, prevented superoxide anion formation, programmed cell death, and the alterations in active and passive tensions with time of overloaded papillary muscles. In conclusion, overstretching appears to be coupled with oxidant stress, expression of Fas, programmed cell death, architectural rearrangement of myocytes, and impairment in force development of the myocardium.
Precision medicine: Clarity for the clinical and biological complexity of Alzheimer’s and Parkinson’s diseases
Authors: Thomas J. Montine, Kathleen S. Montine
Journal: The Journal of Experimental Medicine (2015)

The goal of precision medicine is to deliver optimally targeted and timed interventions tailored to an individual's molecular drivers of disease. This concept has wide currency in cancer care and in some diseases caused by monogenetic mutations, such as cystic fibrosis, and recently has been endorsed by the White House Office of Science and Technology for more widespread application in medicine. Here we describe our vision of how precision medicine can bring greater clarity to the clinical and biological complexity of the two most common neurodegenerative diseases, Alzheimer's disease and Parkinson's disease.
Expression of Lyt-1 antigen on certain murine B cell lymphomas.
Authors: L L Lanier, N L Warner, J A Ledbetter, L A Herzenberg
Journal: The Journal of Experimental Medicine (1981)

Although the Lyt-1 antigen has previously been considered a T cell-specific marker, recent evidence suggests that a population of Thy-1-, Lyt-1+ cells exists in normal lymphoid tissues. In this study, we have observed that the WEHI-55, WEHI-259, and CH5 B cell lymphomas express high levels of the Lyt-1 antigen, as detected by monoclonal antibodies using the fluorescence activated cell sorter. Three other B cell lymphomas of the 11 examined also gave weak but detectable reactions with the anti Lyt-1 monoclonal antibody. Except for the expression of the Lyt-1 antigen, these lymphomas are typical of cells in the B cell lineage with respect to surface phenotype. The Lyt-1 glycoprotein immunoprecipitated from metabolically labeled WEHI-55 cells is similar in structure to the Lyt-1 glycoprotein on thymocytes. These findings are similar to recent reports that B-type human lymphocytic leukemia cells express the putative human homologue of Lyt-1, the Leu-1 antigen.