tbuckley/cabot-search huggingface dataset:
Gene Expression Profiling Identifies Molecular Subtypes of Inflammatory Breast Cancer
Authors: François Bertucci, Pascal Finetti, Jacques Rougemont, Emmanuelle Charafe-Jauffret, Nathalie Cervera, Carole Tarpin, Catherine Nguyen, Luc Xerri, Rémi Houlgatte, Jocelyne Jacquemier, Patrice Viens, Daniel Birnbaum
Journal: Cancer Research (2005)

Abstract Breast cancer is a heterogeneous disease. Comprehensive gene expression profiles obtained using DNA microarrays have revealed previously indistinguishable subtypes of noninflammatory breast cancer (NIBC) related to different features of mammary epithelial biology and significantly associated with survival. Inflammatory breast cancer (IBC) is a rare, particular, and aggressive form of disease. Here we have investigated whether the five molecular subtypes described for NIBC (luminal A and B, basal, ERBB2 overexpressing, and normal breast-like) were also present in IBC. We monitored the RNA expression of ∼8,000 genes in 83 breast tissue samples including 37 IBC, 44 NIBC, and 2 normal breast samples. Hierarchical clustering identified the five subtypes of breast cancer in both NIBC and IBC samples. These subtypes were highly similar to those defined in previous studies and associated with similar histoclinical features. The robustness of this classification was confirmed by the use of both alternative gene set and analysis method, and the results were corroborated at the protein level. Furthermore, we show that the differences in gene expression between NIBC and IBC and between IBC with and without pathologic complete response that we have recently reported persist in each subtype. Our results show that the expression signatures defining molecular subtypes of NIBC are also present in IBC. Obtained using different patient series and different microarray platforms, they reinforce confidence in the expression-based molecular taxonomy but also give evidence for its universality in breast cancer, independently of a specific clinical form.
Multicenter Phase II Study of Irinotecan, Cisplatin, and Bevacizumab in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma
Authors: Manish A. Shah, Ramesh K. Ramanathan, David H. Ilson, Alissa Levnor, David D'Adamo, Eileen O'Reilly, Archie Tse, Robin Trocola, Lawrence Schwartz, Marinela Capanu, Gary K. Schwartz, David P. Kelsen
Journal: Journal of Clinical Oncology (2006)

Purpose Bevacizumab improves survival in several solid tumor malignancies when combined with chemotherapy. We evaluated the efficacy and safety of the addition of bevacizumab to chemotherapy in the treatment of gastric and gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods Forty-seven patients with metastatic or unresectable gastric/GEJ adenocarcinoma were treated with bevacizumab 15 mg/kg on day 1, irinotecan 65 mg/m 2 , and cisplatin 30 mg/m 2 on days 1 and 8, every 21 days. The primary end point was to demonstrate a 50% improvement in time to progression over historical values. Secondary end points included safety, response, and survival. Results Patient characteristics were as follows: median age 59 years (range, 25 to 75); Karnofsky performance status 90% (70% to 100%); male:female, 34:13; and gastric/GEJ, 24:23. With a median follow-up of 12.2 months, median time to progression was 8.3 months (95% CI, 5.5 to 9.9 months). In 34 patients with measurable disease, the overall response rate was 65% (95% CI, 46% to 80%). Median survival was 12.3 months (95% CI, 11.3 to 17.2 months). We observed no increase in chemotherapy related toxicity. Possible bevacizumab-related toxicity included a 28% incidence of grade 3 hypertension, two patients with a gastric perforation and one patient with a near perforation (6%), and one patient with a myocardial infarction (2%). Grade 3 to 4 thromboembolic events occurred in 25% of patients. Although the primary tumor was unresected in 40 patients, we observed only one patient with a significant upper gastrointestinal bleed. Conclusion Bevacizumab can be safely given with chemotherapy even with primary gastric and GEJ tumors in place. The response rate, time to disease progression (TTP), and overall survival are encouraging, with TTP improved over historical controls by 75%. Further development of bevacizumab in gastric and GEJ cancers is warranted.
Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells <i>In vitro</i> through Its Interaction with Ezrin
Authors: Steven Sizemore, Muzaffer Cicek, Nywana Sizemore, Kwok Peng Ng, Graham Casey
Journal: Cancer Research (2007)

Abstract Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms of breast and prostate cancer. The mechanism through which podocalyxin increases cancer aggressiveness remains poorly understood but may involve the interaction of podocalyxin with ezrin, an established mediator of metastasis. Here, we show that overexpression of podocalyxin in MCF7 breast cancer and PC3 prostate cancer cell lines increased their in vitro invasive and migratory potential and led to increased expression of matrix metalloproteases 1 and 9 (MMP1 and MMP9). Podocalyxin expression also led to an increase in mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) activity. To determine the role of ezrin in these podocalyxin-dependent phenotypic events, we first confirmed that podocalyxin formed a complex with ezrin in MCF7 and PC3 cells. Furthermore, expression of podocalyxin was associated with a changed ezrin subcellular localization and increased ezrin phosphorylation. Transient knockdown of ezrin protein abrogated MAPK and PI3K signaling as well as MMP expression and invasiveness in cancer cells overexpressing podocalyxin. These findings suggest that podocalyxin leads to increased in vitro migration and invasion, increased MMP expression, and increased activation of MAPK and PI3K activity in MCF7 and PC3 cells through its ability to form a complex with ezrin. [Cancer Res 2007;67(13):6183–91]
Framingham, SCORE, and DECODE Risk Equations Do Not Provide Reliable Cardiovascular Risk Estimates in Type 2 Diabetes
Authors: Ruth L. Coleman, Richard J. Stevens, Ravi Retnakaran, Rury R. Holman
Journal: Diabetes Care (2007)

Accurate cardiovascular disease (CVD) risk estimates can inform choice of therapeutic strategies for individuals, provided they have been appropriately validated (1). Risk calculators are of particular relevance in diabetic patients given their 2–4 times higher CVD risk compared with the nondiabetic population (2). Framingham Study (3) risk equations for coronary heart disease (CHD) and CVD, based on age, sex, blood pressure, cholesterol (total and HDL), and smoking, with diabetes status as a categorical variable, have been validated prospectively in general populations (4,5) but not in diabetic subjects (6). The Systematic Coronary Risk Evaluation (SCORE) Project risk scores for fatal CHD and CVD (7) appear to overestimate risk in the general population (8,9) and have not been evaluated in diabetes. Following recognition of glycemia as a CVD risk factor (10), the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) Study Group developed a fatal CVD risk equation incorporating glucose tolerance status and fasting plasma glucose (11). We have evaluated these three risk equations in patients with type 2 diabetes using UK Prospective Diabetes Study (UKPDS) data (12).

The UKPDS (12,13) recruited 5,102 of 7,616 people with newly diagnosed type 2 diabetes in 23 U.K. centers and followed them for median 10.4 years (range 6–20). Exclusion criteria included severe vascular disease, myocardial infarction, or stroke within 1 year and major systemic illness. The study received ethical committee approval, conformed to Declaration of …
DYRK1A in Down syndrome: an oncogene or tumor suppressor?
Authors: Yehudit Birger, Shai Izraeli
Journal: Journal of Clinical Investigation (2012)

Children with Down syndrome (DS) have a markedly increased risk of developing acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia compared with that of children without DS. Despite recent breakthroughs, it is not clear which genes on chromosome 21, the chromosome that is trisomic in individuals with DS, cause this predisposition. In this issue of the JCI, Malinge et al. report their loss- and gain-of-function experiments in mouse and human cells that show that increased expression of the kinase encoded by the chromosome 21 gene DYRK1A suppresses the nuclear factor of activated T cells pathway and promotes AMKL. Interestingly, the same protein has been suggested to contribute to the reduced risk of epithelial cancers in adults with DS, leading to the possibility that it could be proleukemic in children and antitumorigenic in adults.
Membrane-bound C4b interacts endogenously with complement receptor CR1 of human red cells.
Authors: T Kinoshita, M E Medof, K Hong, V Nussenzweig
Journal: The Journal of Experimental Medicine (1986)

Activation of the classical complement pathway on the membrane of autologous cells results in the deposition of C4b on their surface and in the assembly of the C3 convertase C4b2a, one of the amplifying enzymes of the cascade. Here we study the sequence of events leading to irreversible inactivation of the potentially harmful C4b bound to human red cells. We show that deposited C4b interacts endogenously with complement receptor type 1 (CR1) present on the membrane of the same red cell. Complexes containing CR1 and C4b are found in extracts of membranes of C4b-bearing red cells after treatment of the intact cells with a bifunctional crosslinking reagent. The amount of complexed CR1 increases with the number of deposited C4b molecules. Only small amounts of free CR1 are observed on red cells bearing as few as 1,900 molecules of C4b, suggesting that the binding avidity between C4b and endogenous CR1 is high. In agreement with this observation, we find that the deposited C4b inhibits the exogenous cofactor activity of the red cell CR1 for the factor I-mediated cleavage of target-bound clustered C3b. The C4b bound to the human red cells is cleaved by the serum enzyme C3b/C4b inactivator (factor I) and a large fragment (C4c) is released in the incubation medium. The cleavage is totally inhibited by mAbs against CR1, showing that the complement receptor is an essential cofactor for the activity of I. When the number of bound C4b per red cell is relatively small (less than 1,000 molecules) the substrate for the enzymatic activity of factor I is mostly or exclusively the C4b bound endogenously to CR1. Indeed, the kinetics or the extent of cleavage of C4b are not affected by greatly augmenting the concentration of exogenous CR1 or of C4b-bearing red cells in the incubation mixture, thereby increasing the frequency of collisions between CR1 on the surface of one cell with C4b deposited on the membrane of a different cell. On the basis of the present and prior observations, we speculate that both DAF and CR1 act endogenously to inactivate the function of autologous red cell-bound C4b and prevent the progression of the cascade. DAF binding prevents the formation of the C3 convertase, C4b2a. The cleavage and irreversible inactivation of C4b only occurs after the concerted activities of endogenous CR1 and serum factor I.(ABSTRACT TRUNCATED AT 400 WORDS)
Morphological and genetic analysis of steatocystoma multiplex in an Asian family with pachyonychia congenita type 2 harbouring a<i>KRT17</i>missense mutation
Authors: M. Kanda, K. Natsuga, W. Nishie, M. Akiyama, A. Nagasaki, T. Shimizu, H. Shimizu
Journal: British Journal of Dermatology (2008)
The Cardiovascular Relevance of Celiac Disease
Authors: Dario Pitocco, Francesco Zaccardi, Francesca Martini, Simona Giubilato, Giovanna Liuzzo, Filippo Crea, Giovanni Ghirlanda
Journal: Diabetes Care (2012)

We read with great interest the recent article by Leeds et al. (1) regarding the effect of the presence of celiac disease (CD) on glycometabolic parameters in type 1 diabetic subjects and, above all, on diabetes-related microvascular complications. Indeed, several epidemiological and genetic studies strongly suggest a more-than-random association between type 1 diabetes and CD (2,3), but no current guidelines encourage different approaches in patients with the coexistence of the …
Hyponatremia and Mortality among Patients on the Liver-Transplant Waiting List
Authors: W. Ray Kim, Scott W. Biggins, Walter K. Kremers, Russell H. Wiesner, Patrick S. Kamath, Joanne T. Benson, Erick Edwards, Terry M. Therneau
Journal: New England Journal of Medicine (2008)

Under the current liver-transplantation policy, donor organs are offered to patients with the highest risk of death.Using data derived from all adult candidates for primary liver transplantation who were registered with the Organ Procurement and Transplantation Network in 2005 and 2006, we developed and validated a multivariable survival model to predict mortality at 90 days after registration. The predictor variable was the Model for End-Stage Liver Disease (MELD) score with and without the addition of the serum sodium concentration. The MELD score (on a scale of 6 to 40, with higher values indicating more severe disease) is calculated on the basis of the serum bilirubin and creatinine concentrations and the international normalized ratio for the prothrombin time.In 2005, there were 6769 registrants, including 1781 who underwent liver transplantation and 422 who died within 90 days after registration on the waiting list. Both the MELD score and the serum sodium concentration were significantly associated with mortality (hazard ratio for death, 1.21 per MELD point and 1.05 per 1-unit decrease in the serum sodium concentration for values between 125 and 140 mmol per liter; P<0.001 for both variables). Furthermore, a significant interaction was found between the MELD score and the serum sodium concentration, indicating that the effect of the serum sodium concentration was greater in patients with a low MELD score. When applied to the data from 2006, when 477 patients died within 3 months after registration on the waiting list, the combination of the MELD score and the serum sodium concentration was considerably higher than the MELD score alone in 32 patients who died (7%). Thus, assignment of priority according to the MELD score combined with the serum sodium concentration might have resulted in transplantation and prevented death.This population-wide study shows that the MELD score and the serum sodium concentration are important predictors of survival among candidates for liver transplantation.
The course of passive elasticity of myocardial tissue following experimental infarction in rabbits and its relation to mechanical dysfunction.
Authors: J D Laird, H P Vellekoop
Journal: Circulation Research (1977)

Given the substantial reserve of normal myocardium, its inability to sustain life in the presence of 30-50% necrosis of the left ventricle (LV) seems a paradox. It is known that dyskinesia of the infarcted area probably plays a dominant role in initiating failure after an infarction. To study this problem, a well defined experimental infarction was produced by cryogenic means in 58 rabbits, and the animals were allowed to recover. Groups of rabbits were killed 4 hours and 1,2,5, or 10 days following infarction. As quickly as possible (within 4 minutes) a sample specimen from the infarcted area was removed from the LV and subjected to a force-elongation test while being bathed in Ringer solution at 37 degrees C equilibrated with 95% O2-5% CO2. The data were interpreted assuming an exponential stress-strain law with constants K and C. Mean values of K of 10.6 +/- 0.94 (SEM) were found for the noninfarcted control group, whereas, rather surprisingly, no significant trend in K over 10 days was found in the infarcted group. Mean values of K +/- SEM for the postinfarction groups were as follows: 4 hours, 9.51 +/- 0.63; 1 day 10.54 +/- 1.13; 2 days, 13.15 +/- 2.28; 5 days, 11.59 +/- 1.36; and over 10 days, 12.93 +/-1.02. The functional implications were estimated with a simple model of the shortening required of the viable muscle during the isovolumic phase. It was found that contractile reserve fell rapidly with increasing infarct size, reaching zero for a 60% infarct when K = 10. With K greater than 100, there was no appreciable reduction in reserve. With a constant infarct size, variation in reserve with the afterload-preload ration was found to be logarithmic.
Intracranial and Abdominal Aortic Aneurysms: Similarities, Differences, and Need for a New Class of Computational Models
Authors: J.D. Humphrey, C.A. Taylor
Journal: Annual Review of Biomedical Engineering (2008)

Intracranial saccular and abdominal aortic aneurysms (ISAs and AAAs, respectively) result from different underlying disease processes and exhibit different rupture potentials, yet they share many histopathological and biomechanical characteristics. Moreover, as in other vascular diseases, hemodynamics and wall mechanics play important roles in the natural history and possible treatment of these two types of lesions. The goals of this review are twofold: first, to contrast the biology and mechanics of intracranial and abdominal aortic aneurysms to emphasize that separate advances in our understanding of each disease can aid in our understanding of the other disease, and second, to suggest that research on the biomechanics of aneurysms must embrace a new paradigm for analysis. That is, past biomechanical studies have provided tremendous insight but have progressed along separate lines, focusing on either the hemodynamics or the wall mechanics. We submit that there is a pressing need to couple in a new way the separate advances in vascular biology, medical imaging, and computational biofluid and biosolid mechanics to understand better the mechanobiology, pathophysiology, and treatment of these lesions, which continue to be responsible for significant morbidity and mortality. We refer to this needed new class of computational tools as fluid-solid-growth (FSG) models.
Genetic background influences murine prostate gene expression: implications for cancer phenotypes
Authors: Daniella Bianchi-Frias, Colin Pritchard, Brigham H Mecham, Ilsa M Coleman, Peter S Nelson
Journal: Genome biology (2007)

Abstract Background Cancer of the prostate is influenced by both genetic predisposition and environmental factors. The identification of genes capable of modulating cancer development has the potential to unravel disease heterogeneity and aid diagnostic and prevention strategies. To this end, mouse models have been developed to isolate the influences of individual genetic lesions in the context of consistent genotypes and environmental exposures. However, the normal prostatic phenotypic variability dictated by a genetic background that is potentially capable of influencing the process of carcinogenesis has not been established. Results In this study we used microarray analysis to quantify transcript levels in the prostates of five commonly studied inbred mouse strains. We applied a multiclass response t -test and determined that approximately 13% (932 genes) exhibited differential expression (range 1.3-190-fold) in any one strain relative to other strains (false discovery rate ≤10%). Expression differences were confirmed by quantitative RT-PCR, or immunohistochemistry for several genes previously shown to influence cancer progression, such as Psca , Mmp7 , and Clusterin . Analyses of human prostate transcripts orthologous to variable murine prostate genes identified differences in gene expression in benign epithelium that correlated with the differentiation state of adjacent tumors. For example, the gene encoding apolipoprotein D, which is known to enhance resistance to cell stress, was expressed at significantly greater levels in benign epithelium associated with high-grade versus low-grade cancers. Conclusion These studies support the concept that the cellular, tissue, and organismal context contribute to oncogenesis and suggest that a predisposition to a sequence of events leading to pathology may exist prior to cancer initiation.
Review of psychosocial stress and asthma: an integrated biopsychosocial approach
Authors: R. J Wright, M. Rodriguez, S. Cohen
Journal: Thorax (1998)

Environmental stressors may impact asthma morbidity through neuroimmunological mechanisms which are adversely impacted and/or buffered y social networks, social support, and psychological functioning. In addition, life stress may impact on health beliefs and behaviours that may affect asthma management. Whereas earlier psychosomatic models have supported a role for psychological stress in contributing to variable asthma morbidity among those with existing disease, a growing appreciation of the interactions between behavioural, neural, endocrine, and immune processes suggest a role for these psychosocial factors in the genesis of asthma as well. While a causal link between stress and asthma has not bee established, this review provides a framework in which we can begin to see links between these systems that might provide new insights to guide future explorations. The complexity of these interactions underscore the need for a multidisciplinary approach which combines the idea that the origin of asthma is purely psychogenic in nature with the antithetical consideration that the biological aspects are all important. These distinctions are artificial, and future research that synthesizes biological, psychological, sociocultural, and family parameters is urgently needed to further our understanding of the rising burden of asthma.
Effect of<i>Ganoderma lucidum</i>capsules on T lymphocyte subsets in football players on “living high−training low”
Authors: Y Zhang, Z Lin, Y Hu, F Wang
Journal: British Journal of Sports Medicine (2007)

Objective: G lucidum is a popular Chinese herb with an impressive array of reputed health benefits. The purpose of this study was to provide information related to the modulating effect of G lucidum capsules on T lymphocyte subsets in football players during a 28-day “living high−training low ”(LHTL) trial and their possible mechanism of action. Methods: Forty male football players were randomly assigned to four groups: control (living at sea level), LHTL1, LHTL2 and LHTL3. The three LHTL groups had stayed in normobaric hypoxic rooms for 28 days. The four groups trained together at sea level. LHTL1, LHTL2 and LHTL3 groups were provided with placebo, G lucidum 10 capsules/day and G lucidum 20 capsules/day, respectively, for 6 weeks (2 weeks baseline supplementation followed by 28 days of the treatment protocol). Lymphocyte subsets were quantitated using flow cytometry. Results: In the LHTL1 group, when the CD4 + /CD8 + ratio was expressed as relative changes from the baseline, a significant decrease was seen following the 28-day trial compared to the baseline. Furthermore, a significant decrease was observed between LHTL1 and control groups at 21 days. In the LHTL2 group, the relative change of CD4 + /CD8 + ratio from the baseline was significantly lower at 28 days compared with the pretrial baseline. Generally, in the LHTL3 group there was a trend for the per cent changes of the CD4 + /CD8 + ratio from the baseline to be higher than the values for the LHTL1 and LHTL2 groups, but this was not significant. Conclusion: LHTL could affect T lymphocyte subsets significantly as a result of the two simultaneous stimuli of physical activity and exposure to hypoxia. The ingestion of G lucidum in the LHTL3 group could help to ameliorate the variation of the CD4 + /CD8 + ratio in LHTL training, and polysaccharides from G lucidum might be the main active components for the cell-mediated immune function.