tbuckley/cabot-search huggingface dataset:
Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
Authors: Matthew G. Rubashkin, Luke Cassereau, Russell Bainer, Christopher C. DuFort, Yoshihiro Yui, Guanqing Ou, Matthew J. Paszek, Michael W. Davidson, Yunn-Yi Chen, Valerie M. Weaver
Journal: Cancer Research (2014)

Extracellular matrix (ECM) stiffness induces focal adhesion assembly to drive malignant transformation and tumor metastasis. Nevertheless, how force alters focal adhesions to promote tumor progression remains unclear. Here, we explored the role of the focal adhesion protein vinculin, a force-activated mechanotransducer, in mammary epithelial tissue transformation and invasion. We found that ECM stiffness stabilizes the assembly of a vinculin-talin-actin scaffolding complex that facilitates PI3K-mediated phosphatidylinositol (3,4,5)-triphosphate phosphorylation. Using defined two- and three-dimensional matrices, a mouse model of mammary tumorigenesis with vinculin mutants, and a novel super resolution imaging approach, we established that ECM stiffness, per se, promotes the malignant progression of a mammary epithelium by activating and stabilizing vinculin and enhancing Akt signaling at focal adhesions. Our studies also revealed that vinculin strongly colocalizes with activated Akt at the invasive border of human breast tumors, where the ECM is stiffest, and we detected elevated mechanosignaling. Thus, ECM stiffness could induce tumor progression by promoting the assembly of signaling scaffolds, a conclusion underscored by the significant association we observed between highly expressed focal adhesion plaque proteins and malignant transformation across multiple types of solid cancer. See all articles in this Cancer Research section, "Physics in Cancer Research."
Psychiatric Manifestations of Paraneoplastic Disorders
Authors: Matthew S. Kayser, Christian G. Kohler, Josep Dalmau
Journal: American Journal of Psychiatry (2010)

Paraneoplastic disorders of the CNS result from immune responses to neuronal proteins expressed by tumors found elsewhere in the body. Limbic encephalitis, one of the most common manifestations of paraneoplastic disorders, is characterized by rapid onset of psychiatric and neurological symptoms that often culminate in severe neurological deterioration. Recent work has described paraneoplastic syndromes with prominent, and sometimes isolated, psychiatric symptoms for which patients are fi rst seen by a psychiatrist. Here the authors review the existing literature on psychiatric and behavioral manifestations of paraneoplastic disorders, the cellular mechanisms underlying these syndromes, and current treatment and outcomes. They also discuss the broad behavioral findings that highlight the need for psychiatrists to be aware of initial presentations of paraneoplastic disorders.
Effect of red blood cell variants on childhood malaria in Mali: a prospective cohort study
Authors: Tatiana M Lopera-Mesa, Saibou Doumbia, Drissa Konaté, Jennifer M Anderson, Mory Doumbouya, Abdoul S Keita, Seidina A S Diakité, Karim Traoré, Michael A Krause, Ababacar Diouf, Samuel E Moretz, Gregory S Tullo, Kazutoyo Miura, Wenjuan Gu, Michael P Fay, Steve M Taylor, Carole A Long, Mahamadou Diakité, Rick M Fairhurst
Journal: The Lancet Haematology (2015)
The Pathogenesis of Mycosis Fungoides
Authors: Michael Girardi, Peter W. Heald, Lynn D. Wilson
Journal: New England Journal of Medicine (2004)

The most common cutaneous lymphoma is mycosis fungoides, a non-Hodgkin's, peripheral T-cell lymphoma. Recent advances in the understanding of the molecular and biologic behavior of T cells in this lymphoma — notably, their ability to home to the skin, function in an activated state, and achieve clonal dominance — have had a tremendous influence on current treatment. In this review, the expanding armamentarium of biologic agents, phototherapeutic and irradiation techniques, and combination regimens available to treat mycosis fungoides is discussed.
Looking for Trouble: Preventive Genomic Sequencing in the General Population and the Role of Patient Choice
Authors: Gabriel Lázaro-Muñoz, John M. Conley, Arlene M. Davis, Marcia Van Riper, Rebecca L. Walker, Eric T. Juengst
Journal: The American Journal of Bioethics (2015)

Advances in genomics have led to calls for developing population-based preventive genomic sequencing (PGS) programs with the goal of identifying genetic health risks in adults without known risk factors. One critical issue for minimizing the harms and maximizing the benefits of PGS is determining the kind and degree of control individuals should have over the generation, use, and handling of their genomic information. In this article we examine whether PGS programs should offer individuals the opportunity to selectively opt out of the sequencing or analysis of specific genomic conditions (the menu approach) or whether PGS should be implemented using an all-or-nothing panel approach. We conclude that any responsible scale-up of PGS will require a menu approach that may seem impractical to some, but that draws its justification from a rich mix of normative, legal, and practical considerations.
Exercise testing in cystic fibrosis: Why (and how)?
Authors: Ds Urquhart
Journal: Journal of the Royal Society of Medicine (2011)

Exercise in CF is associated with improvements in physical and psychological wellbeing. Exercise testing may have an important role in assessing exercise ability and tailoring patient-specific exercise programmes, and exercise-related outcome measures may prove very useful for research intervention studies. Exercise capacity is of known prognostic importance in both adults and children with CF, and the degree of mutual exclusivity that separates fitness from lung function suggests that exercise testing is a vital diagnostic tool for identifying patients at risk of decline.

The question of why exercise test in CF seems self-evident, but how to test is less clear-cut. A variety of field tests exist that are low-cost tests requiring minimal equipment. These act as surrogate tests of exercise capacity and can be submaximal in some cases. The gold standard test is CPET, a maximal test that provides precise exercise data. CPET is, however costly, needs highly specialized equipment and also requires technical expertise to supervise and interpret the test.

The choice of test depends upon the question one is trying to answer. The chosen exercise test should be one that allows maximal exercise to be achieved, and may also be influenced by equipment and expertise that is held locally. Research outcomes may need the precision of CPET, whereas if one is looking for year on year within patient comparison, selection of a field test or incremental treadmill or ergometer test without metabolic measures may be appropriate. A desire for precise and reproducible data on exercise capacity in CF, however, may demand CPET as the test of choice of the future.
Association between qPCR bacterial load and airway inflammation in COPD
Authors: Nisha Rana, Bethan Barker, Koirobi Haldar, Hemu Patel, Vijay Mistry, Mitesh Pancholi, Michael Barer, Christopher Brightling, Mona Bafadhel
Journal: European Respiratory Journal (2013)

Background: In COPD bacterial colonisation is associated with a sputum neutrophilia and increased airway inflammation. Quantitative PCR (qPCR) is more sensitive than culture for bacterial detection. Relationships between sputum inflammatory mediators and pathogens quantified by qPCR in stable state are unclear.

Methods: Sputum from 66 stable COPD patients was analysed for bacterial load (semi-quantitative culture [colony forming units/ml, CFU], qPCR for Haemophilus influenzae [HI], Streptococcus pneumoniae [SP] and Moraxella catarrhalis [MC]), differential cell counts (total cell count [TCC], neutrophil %, eosinophil %) and a panel of inflammatory mediators. Associations between bacterial load and both inflammatory mediators and differential cell counts were explored. Correlations were considered significant if p<0.01.

Results: Positive correlations were found between CFU and TNFα (rs=0.42,p=0.001), IL1β (rs=0.39,p=0.001) and IL10 (rs=0.57,p<0.001). Several positive correlations were found between qPCR HI and inflammatory mediators (table 1) . qPCR MC and qPCR SP did not positively correlate with CFU, sputum cell counts or any sputum inflammatory mediator.

View this table:

Table 1: Correlations between H. influenzae qPCR load and inflammatory mediators





Conclusions: Stable state H. influenzae qPCR load is associated with an increased sputum total cell count, neutrophil percent and inflammatory mediators in COPD. The same associations were not seen with qPCR S. pneumoniae and M. catarrhalis .
Trends in incidence of nonmelanoma skin cancers in Alberta, Canada, 1988-2007
Authors: G.W. Jung, A.I. Metelitsa, D.C. Dover, T.G. Salopek
Journal: British Journal of Dermatology (2010)

Nonmelanoma skin cancer (NMSC) is the most common malignancy affecting caucasian populations and has been seeing global increases in incidence for decades.The objective of this study was to determine trends in incidence of NMSC in Alberta, Canada from 1988 to 2007.A retrospective analysis of patients from Alberta diagnosed with NMSC from 1988 to 2007 inclusive was conducted with data retrieved from the Alberta Cancer Registry (ACR). Sex-, age- and anatomical location-specific incidence rates and trends were examined.From 1988 to 2007, there were 66 192 basal cell carcinomas, 19 959 invasive squamous cell carcinomas (SCC) and 12 494 in situ SCC. ACR coding for the 2007 data was not completed at the time of this study; hence, data from this year were not included in the trend analyses. Incidence of NMSC in women has been stable since 2000 [annual percentage change (APC) 0.08, P = 0.88] and has declined in men since 2001 (APC -1.28, P = 0.026). BCC incidence has been stable since 2000 (APC -0.80, P = 0.09). In situ and invasive SCC also showed a trend towards stabilization in 2000 (APC 0.36, P = 0.77) and 1995 (APC 0.01, P = 0.98), respectively. NMSC primarily affects the elderly and is rarely seen in individuals before the age of 40 years. Although the head and neck region was the location most often involved with NMSC (71.1%), it revealed a stabilizing trend, whereas most other anatomical regions demonstrated an increasing NMSC incidence rate.NMSC incidence in Alberta has stabilized in women and declined in men. As 95-99% of NMSC occurs in patients aged 40 years or older, and with its increased frequency in traditionally clothed areas, the authors recommend regular complete skin examinations starting at 40 years of age.
Survivin 2α: a novel Survivin splice variant expressed in human malignancies
Authors: Hugo Caldas, Laura E Honsey, Rachel A Altura
Journal: Molecular Cancer (2005)

Abstract Background Survivin and its alternative splice forms are involved in critical cellular processes, including cell division and programmed cell death. Survivin is expressed in the majority of human cancers, but minimally in differentiated normal tissues. Expression levels correlate with tumor aggressiveness and resistance to therapy. Results In the present study, we identify and characterize a novel survivin isoform that we designate survivin 2α. Structurally, the transcript consists of 2 exons: exon 1 and exon 2, as well as a 3' 197 bp region of intron 2. Acquisition of a new in-frame stop codon within intron 2 results in an open reading frame of 225 nucleotides, predicting a truncated 74 amino acid protein. Survivin 2α is expressed at high levels in several malignant cell lines and primary tumors. Functional assays show that survivin 2α attenuates the anti-apoptotic activity of survivin. Subcellular localization and immunoprecipitation of survivin 2α suggests a physical interaction with survivin. Conclusion We characterized a novel survivin splice variant that we designated survivin 2α. We hypothesize that survivin 2α can alter the anti-apoptotic functions of survivin in malignant cells. Thus survivin 2α may be useful as a therapeutic tool in sensitizing chemoresistant tumor cells to chemotherapy.
Arhgef1 Is Required by T Cells for the Development of Airway Hyperreactivity and Inflammation
Authors: Jeanette P. Brown, Christian Taube, Nobuaki Miyahara, Toshiyuki Koya, Roberta Pelanda, Erwin W. Gelfand, Raul M. Torres
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein-coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations.To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity.Arhgef1-deficient (Arhgef1-/-) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine. Inflammation was assessed by several parameters that included flow cytometric analysis and histology. Arhgef1-deficient recipients were reconstituted with WT T lymphocytes before sensitization and challenge, and again measured for airway responsiveness and inflammation. Cytokine production in response to specific antigen was measured in cultures of isolated leukocytes from lung and spleen and compared with the levels generated in lung and spleen explant cultures.Arhgef1-/- mice display significantly reduced airway hyperreactivity, Th2 cytokine production, and lung inflammation, despite intact systemic immunity. After airway challenge of Arhgef1-/- mice, antigen-specific T cells were present in mutant lungs, but were found to interact with CD11c+ cells at a significantly reduced frequency. Adoptive transfer of WT T cells into Arhgef1-/- mice restored airway hyperreactivity and inflammation.These data demonstrate that T cells depend on Arhgef1 to promote lung inflammation. Moreover, a deficiency in Arhgef1 results in reduced T cell-CD11c+ antigen-presenting cell interaction, and likely underscores the inability of Arhgef1-/- mice to mount an adaptive immune response to airway challenge.
Activation of the Extracellular-Signal Regulated Protein Kinase Pathway in Human Glomerulopathies
Authors: Takao Masaki, Cosimo Stambe, Prudence A. Hill, John Dowling, Robert C. Atkins, David J. Nikolic-Paterson
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Examined was extracellular-signal regulated kinase (ERK) activation in normal human kidney (<i>n</i> = 2) and a cohort of glomerulopathies by immunohistochemistry staining for the dual-phosphorylated form of ERK (p-ERK). Cell proliferation was determined by expression of the proliferating cell nuclear antigen (PCNA). In normal human kidney, p-ERK was largely restricted to the cytoplasm of cells of the collecting duct (CD). In glomerulopathies, glomerular ERK activation was highly variable. However, there was colocalization of cell proliferation and ERK activation in the glomerular tuft and crescents. Tubular ERK activation in the different glomerulopathies was confined to the CD in areas with normal architecture. In contrast, ERK activation was prominent in tubules and interstitial cells in areas of tubulointerstitial damage. ERK activation was observed in glomerular and interstitial α-smooth muscle actin–positive myofibroblasts, but few macrophages or T cells showed ERK activation. There was a significant correlation between glomerular p-ERK+ and PCNA+ cells and between tubular p-ERK+ and PCNA+ cells. Glomerular p-ERK+ cells correlated with glomerular cellularity and the percentage of glomeruli with segmental lesions. Tubular p-ERK+ cells correlated with renal dysfunction and interstitial fibrosis and tubular atrophy. In conclusion, activation of the ERK pathway in human glomerulopathies correlates with cell proliferation, histologic lesions, and renal dysfunction. ERK activation may promote renal repair through tubular proliferation while promoting renal fibrosis via proliferation of glomerular and interstitial myofibroblasts.
CHILDREN OF SCHIZOPHRENIC PATIENTS : PRELIMINARY OBSERVATIONS ON EARLY DEVELOPMENT
Authors: DAVID E. SOBEL
Journal: American Journal of Psychiatry (1961)

We have observed the early development of children of 2 schizophrenic parents. Three of the 4 children raised by their original schizophrenic parents developed clear-cut signs of depression and irritability in infancy. None of the 4 infants raised by foster parents developed any such clear-cut signs of emotional disorder. Our data suggest that the parental behavior of their schizophrenic mothers was at least partially responsible for the early emotional mal-development observed in their 3 infants. All 3 schizophrenic mothers were consistently depressed with their infants. The "contagion of depression" from mother to infant was discussed and it was suggested that this phenomenon caused an enduring depressive pattern of affective discharge in the infants we observed. It was also noted that all 3 schizophrenic mothers indulged in relatively little active play with their infants and showed relatively little pleasurable responsiveness to their infants. Certain observations suggested to us that a mother with acute catatonic symptoms may have a particularly harmful effect on the physical and emotional growth of an infant. We were also struck by the many separation and deprivation experiences occurring to infants reared by schizophrenic mothers mated to schizophrenic partners. We are continuing our study of infants with 2 schizophrenic parents. This group offers an opportunity to explore a number of hypotheses which we shall comment on in the future.
Effect of Cognitive-Existential Group Therapy on Survival in Early-Stage Breast Cancer
Authors: David W. Kissane, Anthony Love, Allison Hatton, Sidney Bloch, Graeme Smith, David M. Clarke, Patricia Miach, Jill Ikin, Nadia Ranieri, Raymond D. Snyder
Journal: Journal of Clinical Oncology (2004)

Purpose Cognitive-existential group therapy (CEGT) was developed to improve mood and mental attitude toward cancer in women with early-stage breast cancer receiving adjuvant chemotherapy. Given the debate about group therapy's association with increased survival in women with metastatic breast cancer, we were curious to check its effect at a much earlier stage in the cancer journey. Patients and Methods We randomly assigned 303 women with early-stage breast cancer who were receiving adjuvant chemotherapy to either 20 sessions of weekly group therapy plus three relaxation classes (n = 154) or to a control condition of three relaxation classes alone (n = 149). The primary outcome was survival. Results CEGT did not extend survival; the median survival time was 81.9 months (95% CI, 64.8 to 99.0 months) in the group-therapy women and 85.5 months (95% CI, 67.5 to 103.6 months) in the control arm. The hazard ratio for death was 1.35 (95% CI, 0.76 to 2.39; P = .31). In contrast, histology and axillary lymph node status were significant predictors of survival. Low-grade histology yielded a hazard ratio of 0.342 (95% CI, 0.17 to 0.69), and axillary lymph node–negative status yielded a hazard ratio of 0.397 (95% CI, 0.20 to 0.78). Conclusion CEGT does not prolong survival in women with early-stage breast cancer.
Pseudomonas aeruginosa adherence to remodelling respiratory epithelium
Authors: S de Bentzmann, P Roger, E Puchelle
Journal: European Respiratory Journal (1996)

Pseudomonas aeruginosa is an opportunistic organism, which frequently colonizes the respiratory tract of patients with impaired host defence. In cystic fibrosis (CF) patients, this pathogen causes a progressive destructive bronchitis and bronchiolitis and is responsible for high mortality. Normal respiratory epithelium is protected against bacteria via mucus and mucociliary clearance. Alteration of mucociliary clearance and of glycosylation of mucins in CF facilitates the access of bacteria to the underlying airway epithelial cells. Intact respiratory epithelium does not bind P. aeruginosa, whereas injured respiratory epithelium is highly susceptible to P. aeruginosa adherence. We found that the high affinity of respiratory epithelium, from CF and non-CF sources, for P. aeruginosa, during the wound repair process is related to the apical expression of asialo ganglioside M1 (aGM1). The affinity of repairing respiratory epithelium for P. aeruginosa is time-dependent, and is related to transient apical expression of aGM1 at the surface of repairing respiratory epithelial cells. CF respiratory epithelial cells apically express more aGM1 residues with relation to an increased affinity for P. aeruginosa than non CF cells. High epithelial damage followed by repair represents a major cause of P. aeruginosa adherence to airway epithelium in cystic fibrosis. However, P. aerurignosa adherence and colonization are not restricted to cystic fibrosis disease and P. aeruginosa pneumonia may also occur in severely immunocompromised patients, suggesting that epithelial injury and decreased host-response favour the colonization of the airways by P. aeruginosa.
The role of interleukin 1 in growth and metastasis of human cancer xenografts.
Authors: Dina M Elaraj, David M Weinreich, Sheelu Varghese, Markus Puhlmann, Stephen M Hewitt, Nancy M Carroll, Elizabeth D Feldman, Ewa M Turner, H Richard Alexander
Journal: Clinical Cancer Research (2006)

Abstract BACKGROUND: Interleukin 1 (IL-1) is a pluripotent cytokine that promotes angiogenesis, tumor growth, and metastasis in experimental models; its presence in some human cancers is associated with aggressive tumor biology. The purpose of these studies was to characterize the role of IL-1 in human cancers and determine if inhibition of IL-1 via its receptor antagonist, IL-1Ra, alters tumor growth and metastatic potential. METHODS: IL-1 mRNA or protein levels were determined in clinical tumor samples, cancer cell lines, and xenografts using quantitative reverse transcription-PCR or ELISA. Biological activity of tumor-derived IL-1 protein was shown via induction of permeability across endothelial cell monolayers. The effects of recombinant IL-1Ra on tumor lines in culture (cell proliferation and IL-8 secretion) and in xenograft models (tumor growth, metastatic potential, and intratumoral levels of IL-8 and VEGF) were characterized. The effects of IL-1Ra-mediated regression of xenograft growth on angiogenic proteins (IL-8 and VEGF) were evaluated in an IL-1-producing melanoma (SMEL) xenograft model. RESULTS: IL-1 mRNA was highly expressed in more than half of all tested metastatic human tumor specimens including non-small-cell lung carcinoma, colorectal adenocarcinoma, and melanoma tumor samples. Constitutive IL-1 mRNA expression was identified in several cancer cell lines; tumor supernatant from these cell lines produced a significant increase in endothelial cell monolayer permeability, a hallmark event in early angiogenesis, in an IL-1-dependent manner. Moreover, systemic recombinant IL-1Ra resulted in significant inhibition of xenograft growth and neovessel density of IL-1-producing, but not non-IL-1-producing, tumor cell lines. Subsequent analysis of SMEL, a melanoma cell line with constitutive IL-1 production, showed that neither exogenous IL-1 nor IL-1Ra altered tumor cell proliferation rates in vitro. Gene expression analyses of IL-1Ra-treated SMEL xenografts showed a &amp;gt;3-fold down-regulation of 100 genes compared with control including a marked down-regulation of IL-8 and VEGF. CONCLUSIONS: These data show that the IL-1 gene is frequently expressed in metastases from patients with several types of human cancers. IL-1Ra inhibits xenograft growth in IL-1-producing tumors but has no direct antiproliferative effects in vitro; decreased tumor levels of IL-8 and VEGF may be an early surrogate of IL-1Ra-mediated antitumor activity. IL-1Ra may have a role alone or with other agents in the treatment of human cancers.