tbuckley/cabot-search huggingface dataset:
Novel Metastasis-Related Gene CIM Functions in the Regulation of Multiple Cellular Stress–Response Pathways
Authors: Kiyoshi Yanagisawa, Hiroyuki Konishi, Chinatsu Arima, Shuta Tomida, Toshiyuki Takeuchi, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Hirotaka Osada, Takashi Takahashi
Journal: Cancer Research (2010)

Various stresses of the tumor microenvironment produced by insufficient nutrients, pH, and oxygen can contribute to the generation of altered metabolic and proliferative states that promote the survival of metastatic cells. Among many cellular stress-response pathways activated under such conditions are the hypoxia-inducible factor (HIF) pathway and the unfolded protein response (UPR), which is elicited as a response to endoplasmic reticulum (ER) stress. In this study, we report the identification of a novel cancer invasion and metastasis-related gene (hereafter referred to as CIM, also called ERLEC1), which influences both of these stress-response pathways to promote metastasis. CIM was identified by comparing the gene expression profile of a highly metastatic human lung cancer cell line with its weakly metastatic parental clone. We showed that CIM is critical for metastatic properties in this system. Proteomic approaches combined with bioinformatic analyses revealed that CIM has multifaceted roles in controlling the response to hypoxia and ER stress. Specifically, CIM sequestered OS-9 from the HIF-1α complex and PHD2, permitting HIF-1α accumulation by preventing its degradation. Ectopic expression of CIM in lung cancer cells increased their tolerance to hypoxia. CIM also modulated UPR through interaction with the key ER stress protein BiP, influencing cell proliferation under ER stress conditions. Our findings shed light on how tolerance to multiple cellular stresses at a metastatic site can be evoked by an integrated mechanism involving CIM, which can function to coordinate those responses in a manner that promotes metastatic cell survival.
T-cell co-stimulatory molecules: their role in allergic immune reactions
Authors: T. Kallinich, K. C. Beier, U. Wahn, P. Stock, E. Hamelmann
Journal: European Respiratory Journal (2007)

The development of allergic diseases, such as allergic asthma, depends upon the initiation and maintenance of T-helper cell type-2-skewed allergen-specific immune reactions. Although it is clear that susceptibility to this process is under genetic and environmental control, the fine-tuning and regulation of the type-2 T-helper cell immune response is not yet fully understood. In this second article in the present series, current understanding regarding the involvement of T-cells and antigen-presenting cells is summarised, with emphasis on the interaction between these two types of immune regulatory cells by means of co-stimulatory molecules.
Enhancer of Zeste 2 as a Marker of Preneoplastic Progression in the Breast
Authors: Lei Ding, Celina G. Kleer
Journal: Cancer Research (2006)

Abstract Amplification of the Polycomb group transcriptional repressor Enhancer of Zeste 2 (EZH2) occurs in various malignancies including breast cancer, where its overexpression is associated with poor outcome. We found that EZH2 is up-regulated in ductal carcinoma in situ, atypical ductal hyperplasia, and even morphologically normal breast epithelial cells from women who have an increased risk of breast cancer. This review discusses how EZH2 may promote neoplastic conversion and it surveys the evidence suggesting that EZH2 may offer a clinical tool to help identify patients at risk for developing breast cancer before precursor lesions are histologically evident. (Cancer Res 2006; 66(19): 9352-5)
Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration
Authors: Nick Sheron, George Bird, John Koskinas, Bernard Portmann, Miroslav Ceska, Ivan Lindley, Roger William
Journal: Hepatology (1993)

Acute alcoholic hepatitis is characterized by a unique degree of liver neutrophil infiltration, often accompanied by marked peripheral neutrophilia in the absence of demonstrable bacterial or fungal infection. In this study we assayed plasma and tissue levels of a potent neutrophil activator and chemotaxin, interleukin-8, in patients with a spectrum of alcoholic liver diseases and in normal and diseased control subjects. Levels of circulating interleukin-8 were undetectable in normal subjects but highly elevated in patients with alcoholic hepatitis, particularly in those who died (geometric mean = 600 ng/L; confidence interval = 323 to 1,120 vs. geometric mean = 184 ng/L; confidence interval = 114 to 309 in survivors). Levels correlated with biochemical indicators of severe disease (bilirubin: R = 0.38; international prothrombin ratio: R = 0.28; white blood cell count: R = 0.35; creatinine: R = 0.34) and with tumor necrosis factor-alpha (R = 0.43) and soluble tumor necrosis factor receptors (p55; R = 0.59). In contrast, moderate elevations in the levels of circulating interleukin-8 were seen in alcoholic cirrhosis (geometric mean = 93 ng/L; confidence interval = 40 to 213) and in alcoholic patients undergoing alcohol withdrawal (geometric mean = 137 ng/L; confidence interval = 72 to 259). Levels in nonalcoholic inflammatory liver disease were comparatively low (geometric mean = 17 ng/L; confidence interval = 10 to 29).(ABSTRACT TRUNCATED AT 250 WORDS)
Emergence of a New Pathogenic Ehrlichia Species, Wisconsin and Minnesota, 2009
Authors: Bobbi S. Pritt, Lynne M. Sloan, Diep K. Hoang Johnson, Ulrike G. Munderloh, Susan M. Paskewitz, Kristina M. McElroy, Jevon D. McFadden, Matthew J. Binnicker, David F. Neitzel, Gongping Liu, William L. Nicholson, Curtis M. Nelson, Joni J. Franson, Scott A. Martin, Scott A. Cunningham, Christopher R. Steward, Kay Bogumill, Mary E. Bjorgaard, Jeffrey P. Davis, Jennifer H. McQuiston, David M. Warshauer, Mark P. Wilhelm, Robin Patel, Vipul A. Trivedi, Marina E. Eremeeva
Journal: New England Journal of Medicine (2011)

Ehrlichiosis is a clinically important, emerging zoonosis. Only Ehrlichia chaffeensis and E. ewingii have been thought to cause ehrlichiosis in humans in the United States. Patients with suspected ehrlichiosis routinely undergo testing to ensure proper diagnosis and to ascertain the cause.
Early Crohn disease: a proposed definition for use in disease-modification trials
Authors: Laurent Peyrin-Biroulet, Edward V Loftus, Jean-Frederic Colombel, William J Sandborn
Journal: Gut (2010)

Crohn disease is a chronic condition characterised by intestinal inflammation and progressive bowel damage associated with impaired functioning.

In rheumatoid arthritis, which shares some common aetiological pathways and treatments with Crohn disease, treatment goals no longer include symptom control alone, but also alteration of the biological processes underlying synovial inflammation and progressive structural destruction, thereby preventing structural joint damage and functional decline.1 Analogous disease-modifying treatment goals for Crohn disease are currently being conceptualised and may include prevention of structural bowel damage (stricture, fistula, abscess) and impaired gastrointestinal physiology (ie, maintaining normal gastrointestinal physiology).2 3

In order to achieve disease modification, an effective intervention must occur at the right time, that is, before the development of bowel damage and impaired functioning. While it has been said in this context ‘the earlier, the better’, there is no formal definition of early Crohn disease.4 This article will review the rationale for defining early Crohn disease and the rationale for specifically targeting early Crohn disease from both immunopathological and clinical points of view, using rheumatoid arthritis (another chronic, progressive, destructive disease), as an example. We will then propose a definition of early Crohn disease and briefly discuss its potential application in future clinical trials.

Studies from referral centres have demonstrated that the clinical features of Crohn disease change over time with a decreasing frequency of inflammatory (non-stricturing non-penetrating) disease behaviour and an increasing frequency of stricturing and/or penetrating disease behaviour (disease progression).5 6 Population-based studies have demonstrated that more than 50% of adult patients with Crohn disease develop stricturing or penetrating intestinal complications within 20 years of diagnosis7 and similarly these complications occur in more than 50% of children after a median follow-up of 84 months.8 The development of these complications is associated with a need for surgical resection. …
Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia
Authors: Renate Kirschner-Schwabe, Claudio Lottaz, Jörn Tödling, Peter Rhein, Leonid Karawajew, Cornelia Eckert, Arend von Stackelberg, Ute Ungethüm, Dennis Kostka, Andreas E. Kulozik, Wolf-Dieter Ludwig, Günter Henze, Rainer Spang, Christian Hagemeier, Karl Seeger
Journal: Clinical Cancer Research (2006)

Abstract Purpose: In childhood acute lymphoblastic leukemia (ALL), ∼25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood. Experimental Design: Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Münster study group. Results: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern. We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G2-M phase cells and this correlated well with the expression level of cell cycle genes. Conclusions: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes. The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.
Supramaximal flow in asthmatic patients
Authors: H. Sala, A. Fernandez, S. Guardia, A. Gonzalez, D. Rodenstein
Journal: European Respiratory Journal (2002)

In normal subjects supramaximal flows (SF) are known to be correlated with flow limitation. To further understand the mechanisms involved in SF this correlation and the influence of salbutamol and methacholine administration on SF have been investigated in asthmatic subjects. Protocol A involved obtaining basal maximal expiratory flow/volume curves and interrupted curves through a fast valve from 36 asthmatic patients. Maximal flow at 50% of forced vital capacity (V'max50) increase (deltaV'max50) was compared between basal curves and envelope curves passing through SF peaks obtained after each interruption. Protocol B involved the study of 33 asthmatic patients after salbutamol administration and 12 asthmatic patients after methacholine challenge. DeltaV'max50 between basal versus interrupted curves were analysed (deltaV'max50B). Similar procedures were performed after salbutamol (deltaV'max50S) and after methacholine administration (deltaV'max50M). A significant negative correlation between forced expiratory volume in one second and deltaV'max50 was observed. SF decreased significantly after salbutamol administration and increased significantly after methacholine. The results of this study suggest that in asthmatic patients participation of "pendelluft" in SF increases as airflow limitation increases.
Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma
Authors: Deborah A. Thomas, Susan O'Brien, Jorge Cortes, Francis J. Giles, Stefan Faderl, Srdan Verstovsek, Alessandra Ferrajoli, Charles Koller, Miloslav Beran, Sherry Pierce, Chul S. Ha, Fernando Cabanillas, Michael J. Keating, Hagop Kantarjian
Journal: Blood (2004)
Comparing hospital and telephone follow-up after treatment for breast cancer: randomised equivalence trial
Authors: K. Beaver, D. Tysver-Robinson, M. Campbell, M. Twomey, S. Williamson, A. Hindley, S. Susnerwala, G. Dunn, K. Luker
Journal: BMJ (2009)

<b>Objective</b> To compare traditional hospital follow-up with telephone follow-up by specialist nurses after treatment for breast cancer. <b>Design</b> A two centre randomised equivalence trial in which women remained in the study for a mean of 24 months. <b>Setting</b> Outpatient clinics in two NHS hospital trusts in the north west of England <b>Participants</b> 374 women treated for breast cancer who were at low to moderate risk of recurrence. <b>Interventions</b> Participants were randomised to traditional hospital follow-up (consultation, clinical examination, and mammography as per hospital policy) or telephone follow-up by specialist nurses (consultation with structured intervention and mammography according to hospital policy). <b>Main outcome measures</b> Psychological morbidity (state-trait anxiety inventory, general health questionnaire (GHQ-12)), participants' needs for information, participants' satisfaction, clinical investigations ordered, and time to detection of recurrent disease. <b>Results</b> The 95% confidence interval for difference in mean state-trait scores adjusted for treatment received (−3.33 to 2.07) was within the predefined equivalence region (−3.5 to 3.5). The women in the telephone group were no more anxious as a result of foregoing clinic examinations and face-to-face consultations and reported higher levels of satisfaction than those attending hospital clinics (intention to treat P&lt;0.001). The numbers of clinical investigations ordered did not differ between groups. Recurrences were few (4.5%), with no differences between groups for time to detection (median 60.5 (range 37-131) days in hospital group <i>v</i> 39.0 (10-152) days in telephone group; P=0.228). <b>Conclusions</b> Telephone follow-up was well received by participants, with no physical or psychological disadvantage. It is suitable for women at low to moderate risk of recurrence and those with long travelling distances or mobility problems and decreases the burden on busy hospital clinics. <b>Trial registration</b> National Cancer Research Institute 1477.
Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection
Authors: Wanqiu Hou, Hyun Seok Kang, Byung S. Kim
Journal: The Journal of Experimental Medicine (2009)

Persistent viral infection and its associated chronic diseases are a global health concern. Interleukin (IL) 17–producing Th17 cells have been implicated in the pathogenesis of various autoimmune diseases, and in protection from bacterial or fungal infection. However, the role of Th17 cells in persistent viral infection remains unknown. We report that Th17 cells preferentially develop in vitro and in vivo in an IL-6–dependent manner after Theiler’s murine encephalomyelitis virus infection. Th17 cells promote persistent viral infection and induce the pathogenesis of chronic demyelinating disease. IL-17 up-regulates antiapoptotic molecules and, consequently, increases persistent infection by enhancing the survival of virus-infected cells and blocking target cell destruction by cytotoxic T cells. Neutralization of IL-17 augments virus clearance by eliminating virus-infected cells and boosting lytic function by cytotoxic T cells, leading to the prevention of disease development. Thus, these results indicate a novel pathogenic role of Th17 cells via IL-17 in persistent viral infection and its associated chronic inflammatory diseases.
What a Tangled Web We Weave: Emerging Resistance Mechanisms to Inhibition of the Phosphoinositide 3-Kinase Pathway
Authors: Samuel J. Klempner, Andrea P. Myers, Lewis C. Cantley
Journal: Cancer Discovery (2013)

The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently mutated pathways in cancer, and is actively being pursued as a therapeutic target. Despite the importance of the PI3K pathway in cancer, durable responses to PI3K pathway-targeted therapies are uncommon with monotherapy. Several in vitro and xenograft models have elucidated compensatory signaling and genomic changes which may limit the therapeutic effectiveness of PI3K inhibitors in the clinic. Future clinical trials with prospective evaluation of tumor signaling and genomic changes are likely to identify novel resistance mechanisms as well as subsets of patients who may derive maximal benefit from PI3K pathway inhibitors.There are multiple ongoing clinical trials targeting the PI3K pathway members in several malignancies. This review summarizes the known mechanisms of resistance to targeting the PI3K pathway. Understanding of resistance mechanisms will help to inform more rational clinical trial design to optimize the clinical impact of targeting the PI3K pathway in cancer.
Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency
Authors: Nicole Draper, Elizabeth A Walker, Iwona J Bujalska, Jeremy W Tomlinson, Susan M Chalder, Wiebke Arlt, Gareth G Lavery, Oliver Bedendo, David W Ray, Ian Laing, Ewa Malunowicz, Perrin C White, Martin Hewison, Philip J Mason, John M Connell, Cedric H L Shackleton, Paul M Stewart
Journal: Nature Genetics (2003)
p38 Mitogen-Activated Protein Kinase Activation and Cell Localization in Human Glomerulonephritis
Authors: Cosimo Stambe, David J. Nikolic-Paterson, Prudence A. Hill, John Dowling, Robert C. Atkins
Journal: Journal of the American Society of Nephrology (2004)

Activation of the p38 mitogen-activated protein kinase (MAPK) signal transduction pathway plays an important role in the inflammatory response. It was postulated that p38 MAPK is important in the pathogenesis of human glomerulonephritis and contributes to the development of renal injury. p38 MAPK activation was examined by immunodetection for dual phosphorylated p38 (p-p38) in normal human kidney and 77 renal biopsy specimens encompassing a wide spectrum of glomerulonephritides. In normal kidney, p-p38 immunostaining was restricted to the nuclei of a small number of podocytes, parietal epithelial cells, and tubular cells. There was a dramatic increase in the number of p-p38-positive cells in glomeruli and tubules in nonproliferative and proliferative glomerulonephritis and a substantial increase in the number of interstitial p-p38-positive cells in proliferative glomerulonephritis. Double immunostaining identified p38 activation in intrinsic renal cells (podocytes and endothelial and tubular cells), infiltrating macrophage and neutrophils, and myofibroblasts. Renal failure correlated with the number of p-p38-positive glomerular, tubular, and interstitial cells. Proteinuria correlated with the number of p-p38-positive tubular and interstitial cells and the number of p-p38-positive podocytes in nonproliferative glomerulonephritis. Furthermore, glomerular p38 activation correlated with segmental proliferative and necrotic lesions, and interstitial p38 activation correlated with the degree of interstitial inflammation. In conclusion, activation of p38 MAPK in intrinsic renal cells and infiltrating leukocytes correlated with renal dysfunction and histopathology, suggesting an important pathogenic role for p38 MAPK activation in human glomerulonephritis.
Précis of<i>Semantic Cognition: A Parallel Distributed Processing Approach</i>
Authors: Timothy T. Rogers, James L. McClelland
Journal: Behavioral and Brain Sciences (2008)

Abstract In this précis of our recent book, Semantic Cognition: A Parallel Distributed Processing Approach (Rogers &amp; McClelland 2004), we present a parallel distributed processing theory of the acquisition, representation, and use of human semantic knowledge. The theory proposes that semantic abilities arise from the flow of activation among simple, neuron-like processing units, as governed by the strengths of interconnecting weights; and that acquisition of new semantic information involves the gradual adjustment of weights in the system in response to experience. These simple ideas explain a wide range of empirical phenomena from studies of categorization, lexical acquisition, and disordered semantic cognition. In this précis we focus on phenomena central to the reaction against similarity-based theories that arose in the 1980s and that subsequently motivated the “theory-theory” approach to semantic knowledge. Specifically, we consider (1) how concepts differentiate in early development, (2) why some groupings of items seem to form “good” or coherent categories while others do not, (3) why different properties seem central or important to different concepts, (4) why children and adults sometimes attest to beliefs that seem to contradict their direct experience, (5) how concepts reorganize between the ages of 4 and 10, and (6) the relationship between causal knowledge and semantic knowledge. The explanations our theory offers for these phenomena are illustrated with reference to a simple feed-forward connectionist model. The relationships between this simple model, the broader theory, and more general issues in cognitive science are discussed.
Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis
Authors: W Q Gan
Journal: Thorax (2004)

<b>Background:</b> Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD. <b>Methods:</b> A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV<sub>1</sub>) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-α (TNF-α), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model. <b>Results:</b> Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-α levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)). <b>Conclusions:</b> Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.