tbuckley/cabot-search huggingface dataset:
Frequent Genetic Alterations at the Microsatellite Level in Cytologic Sputum Samples of Patients with Idiopathic Pulmonary Fibrosis
Authors: DIMITRIS A. VASSILAKIS, GEORGE SOURVINOS, DEMETRIOS A. SPANDIDOS, NIKOLAOS M. SIAFAKAS, DEMOSTHENES BOUROS
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology associated with DNA damage and malignancy. Bronchogenic carcinoma is the cause of death in 10% to 13% of IPF patients. Microsatellite instability (MSI) and loss of heterozygosity (LOH) are frequently detected in cancers. If these genetic alterations could be observed in IPF, they might explain the higher relative risk of lung cancer in this disease. We investigated the incidence of MSI and LOH in sputum cytologic specimens from 26 IPF patients and 26 healthy, matched subjects, using 10 highly polymorphic microsatellite markers. The electrophoretic pattern of each specimen was compared with that of corresponding peripheral blood. Thirteen (50%) patients showed genetic alterations, consisting either of MSI or LOH. Five (19%) patients exhibited MSI and 10 (39%) exhibited LOH in at least one microsatellite marker. Three (12%) patients showed LOH in more than one marker. None of the healthy subjects exhibited genetic alterations in the studied markers. No correlation was found between the detected genetic alterations and age, disease duration, blood gases, or spirometric parameters of the patients. Our findings suggest that the genetic alterations that we studied are frequent in IPF, are apparently unrelated to the severity of the disease, and may be related to tumorigenesis.
Antitumor Activity of a Small-Molecule Inhibitor of Human Silent Information Regulator 2 Enzymes
Authors: Birgit Heltweg, Tonibelle Gatbonton, Aaron D. Schuler, Jeff Posakony, Hongzhe Li, Sondra Goehle, Ramya Kollipara, Ronald A. DePinho, Yansong Gu, Julian A. Simon, Antonio Bedalov
Journal: Cancer Research (2006)

SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein. Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2. Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest. Treatment of BCL6-expressing Burkitt lymphoma cells with cambinol as a single agent induced apoptosis, which was accompanied by hyperacetylation of BCL6 and p53. Because acetylation inactivates BCL6 and has the opposite effect on the function of p53 and other checkpoint pathways, the antitumor activity of cambinol in Burkitt lymphoma cells may be accomplished through a combined effect of BCL6 inactivation and checkpoint activation. Cambinol was well tolerated in mice and inhibited growth of Burkitt lymphoma xenografts. Inhibitors of NAD-dependent deacetylases may constitute novel anticancer agents.
Frailty and Protein-Energy Wasting in Elderly Patients with End Stage Kidney Disease
Authors: Jun Chul Kim, Kamyar Kalantar-Zadeh, Joel D. Kopple
Journal: Journal of the American Society of Nephrology (2012)

Older people constitute an increasingly greater proportion of patients with advanced CKD, including those patients undergoing maintenance dialysis treatment. Frailty is a biologic syndrome of decreased reserve and resistance to stressors that results from cumulative declines across multiple physiologic systems and causes vulnerability to adverse outcomes. Frailty is common in elderly CKD patients, and it may be associated with protein-energy wasting (PEW), sarcopenia, dynapenia, and other complications of CKD. Causes of frailty with or without PEW in the elderly with CKD can be classified into three categories: causes primarily caused by aging per se, advanced CKD per se, or a combination of both conditions. Frailty and PEW in elderly CKD patients are associated with impaired physical performance, disability, poorer quality of life, and reduced survival. Prevention and treatment of these conditions in the elderly CKD patients often require a multifaceted approach. Here, we examine the causes and consequences of these conditions and examine the interplay between frailty and PEW in elderly CKD patients.
Age-related difference in myocardial function and inflammation in a rat model of myocardial ischemia–reperfusion
Authors: P Liu
Journal: Cardiovascular Research (2002)

Objective: Aging is associated with a reduced tolerance to myocardial ischemia reperfusion injury when compared to the young adult. However, there is very little information in the literature regarding age-related changes in myocardial function and inflammation during myocardial ischemia–reperfusion (MI/R) in vivo. Methods: We examined age-related differences in myocyte apoptosis and the inflammatory response in a rat model of myocardial ischemia–reperfusion (MI/R). The aged (19 months) and young (4 months) male F344 BN rats were subjected to 30 min of myocardial ischemia by ligating the left main coronary artery, followed by release of the ligature and 4 h of reperfusion. Four experimental groups, e.g. young sham control, aged sham control, young rats subjected to MI/R, and aged rats subjected to MI/R, were studied. Results: MI/R induced a 78% increase in circulating leukocytes and a 30% increase in superoxide generation in the ischemic region of the heart of young rats, when compared to aged rats. Moreover, the arrhythmia scores were higher in young rats than in aged rats (P = 0.058) following MI/R. There was no difference in hemodynamics between young sham and aged sham rats. However, the cardiac index was decreased by 34% at 3 h of reperfusion and by 33% at 4 h of reperfusion in aged rats, when compared to young rats following MI/R. Furthermore, stroke volume index was decreased by 54, 56, and 65% at 2, 3, and 4 h of reperfusion in aged rats, respectively, when compared that of young rats subjected to MI/R. There was an enhanced myocyte apoptosis, as indicated by ELISA and TUNEL staining in the myocardium of aged rats compared to young rats following MI/R. Interestingly, RT-PCR analysis indicated that MI/R significantly increased the ratio of Bax mRNA to Bcl-2 mRNA in aged rats compared to that of young rats (3.51 vs. 0.74). Conclusion: MI/R is associated with an increase in circulating leukocytes and generation of superoxide in the peri-ischemic areas of the heart of young rats, compared to aged rats. However, MI/R induces a significant decrease in cardiac index and stroke volume index in aged rats, when compared to young rats following MI/R. Furthermore, aged rats exhibit an increase in the ratio of Bax mRNA to Bcl-2 mRNA and cardiomyocyte apoptosis following MI/R, which may explain, at least in part, the enhanced myocardial dysfunction.
Kupffer cell activity and hepatic microvascular events after acute ethanol ingestion in mice
Authors: Hiroshi Eguchi, Patricia A. McCuskey, Robert S. McCuskey
Journal: Hepatology (1991)

After acute ethanol ingestion in C57Bl/6 mice, phagocytic activity of Kupffer cells and hepatic microcirculation were examined by in vivo and electron microscopy. A ratio of Kupffer cells that phagocytosed 0.8 micron fluorescent latex particles to sinusoids containing blood flow (number of Kupffer cells/number of sinusoids containing blood flow) was used as a measure of Kupffer cell phagocytic activity. Three hours after ingestion of 1 gm/kg ethanol, number of Kupffer cells/number of sinusoids containing blood flow increased in both periportal and centrilobular regions by 62% and 66%, respectively, and blood ethanol was no longer detectable. Ultrastructurally, activation of KC was evidenced by the presence of many pseudopodia and filopodia. Numbers of swollen endothelial cells were increased in both regions by 249% and 174%. Interruption of sinusoidal blood flow by leukocytes was aggravated in both regions by 127% and 167%. Thirty minutes and 3 hr after ingestion of 4 gm/kg ethanol, no significant increase in number of Kupffer cells/number of sinusoids containing blood flow was seen, although number of Kupffer cells were also activated as seen with electron microscopy. An increased number of swollen endothelial cells was observed in both regions by 100% and 71% by 30 min and by 200% and 384% by 3 hr. The interruption of sinusoidal blood flow by leukocytes was also increased (periportal = 161%, centrilobular = 196%) as were sticking or plugging leukocytes in sinusoids (periportal = 320%, centrilobular = 120%) by 3 hr. The diameter of centrilobular sinusoids was decreased by 3 hr. Latex particles and platelets were attached to the sinusoidal wall after both low and high dosing.(ABSTRACT TRUNCATED AT 250 WORDS)
An <i>In vivo</i> Tumor Model Exploiting Metabolic Response as a Biomarker for Targeted Drug Development
Authors: Carleen Cullinane, Donna S. Dorow, Maya Kansara, Nelly Conus, David Binns, Rodney J. Hicks, Leonie K. Ashman, Grant A. McArthur, David M. Thomas
Journal: Cancer Research (2005)

Abstract In vivo models that recapitulate oncogene-dependent tumorigenesis will greatly facilitate development of molecularly targeted anticancer therapies. We have developed a model based on activating mutations in c-KIT in gastrointestinal stromal tumors (GISTs). This model comprises murine tumors of FDC-P1 cell lines expressing c-KIT mutations that render the tumors either responsive (V560G) or resistant (D816V) to the small-molecule c-KIT inhibitor, imatinib. Clinically, GIST response to imatinib is associated with rapid reduction in fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), preceding changes in conventional response criteria by several weeks. Using the FDC-P1 model in small animal PET, FDG uptake into tumors expressing the c-KIT V560G mutation was significantly reduced as early as 4 hours after imatinib treatment. In contrast, no change in FDG uptake was observed in resistant c-KIT D816V-expressing tumors after 48 hours of imatinib treatment. Consistent with the PET results, expression of the glucose transporter, GLUT1, was significantly reduced in V560G tumors at 4 hours, preceding changes in markers of proliferation by several hours. In vitro, imatinib treatment of V560G cells resulted in a reduction of glucose transporter numbers at the cell surface and decreased glucose uptake well before changes in cell viability. Notably, decreased ambient glucose concentrations enhanced the cytotoxic effect of imatinib. Taken together, these data account for the rapidity and significance of the PET response to imatinib and suggest that metabolic effects may contribute to imatinib cytotoxicity. Further, the FDC-P1 model represents a very useful paradigm for molecularly targeted drug development.
Myc is required for β-catenin-mediated mammary stem cell amplification and tumorigenesis
Authors: Mejdi Moumen, Aurélie Chiche, Charles Decraene, Valérie Petit, Alberto Gandarillas, Marie-Ange Deugnier, Marina A Glukhova, Marisa M Faraldo
Journal: Molecular Cancer (2013)

Basal-like breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Recent studies have linked activation of the Wnt/β-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5ΔNβcat previously generated by our team present a constitutive activation of Wnt/β-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5ΔNβcat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers.Microarray analysis was used to compare K5ΔNβcat mouse tumors to human breast tumors, mammary cancer cell lines and the tumors developed in other mouse models. Cre-Lox approach was employed to delete Myc from the mammary basal cell layer of K5ΔNβcat mice. Stem cell amplification in K5ΔNβcat mouse mammary epithelium was assessed with 3D-culture and transplantation assays.Histological and microarray analyses of the mammary lesions of K5ΔNβcat females revealed their high similarity to a subset of basal-like human breast tumors with squamous differentiation. As in human basal-like carcinomas, the Myc pathway appeared to be activated in the mammary lesions of K5ΔNβcat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5ΔNβcat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5ΔNβcat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis.These results strongly indicate that β-catenin-induced stem cell amplification and tumorigenesis rely ultimately on the Myc pathway activation and reinforce the hypothesis that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumors.
Endogenous Bradykinin Contributes to Increased Plasminogen Activator Inhibitor 1 Antigen following Hemodialysis
Authors: Annis M. Marney, Ji Ma, James M. Luther, T. Alp Ikizler, Nancy J. Brown
Journal: Journal of the American Society of Nephrology (2009)

Oxidative stress and inflammation predict cardiovascular events in chronic hemodialysis patients. Hemodialysis activates the kallikrein-kinin system, increasing bradykinin. Bradykinin promotes inflammation but also stimulates endothelial release of tissue-plasminogen activator and inhibits platelet aggregation. Understanding the detrimental and beneficial effects of endogenous bradykinin during hemodialysis has implications for the treatment of cardiovascular disease in the hemodialysis population. To test the hypothesis that bradykinin contributes to the inflammatory and fibrinolytic responses to dialysis, we conducted a double-blind, randomized, placebo-controlled crossover study comparing the effect of the bradykinin B(2) receptor blocker HOE-140 with vehicle on markers of oxidative stress, inflammation, fibrinolysis, and coagulation in nine hemodialysis patients without coronary artery disease. Bradykinin receptor antagonism did not affect the mean arterial pressure or heart rate response to dialysis. Monocyte chemoattractant protein 1 (MCP-1) peaked postdialysis; HOE-140 blunted the increase in MCP-1 (5.9 +/- 5.9 versus 25.6 +/- 20.1 pg/ml, P = 0.01). HOE-140 also abolished the increase in plasminogen activator inhibitor 1 (PAI-1) antigen observed at the end of dialysis. In contrast, HOE-140 significantly accentuated the effect of dialysis on F(2)-isoprostanes and P-selectin. Taken together, these results suggest that endogenous bradykinin contributes to increases in MCP-1 and PAI-1 antigen after hemodialysis via its B(2) receptor. Factors that increase the production of bradykinin or decrease its degradation may enhance the inflammatory response to hemodialysis.
PHARMACODYNAMIC EFFECTS OF SWITCHING THERAPY IN PCI PATIENTS WITH HIGH ON TREATMENT PLATELET REACTIVITY AND GENOTYPE VARIATION: HIGH CLOPIDOGREL DOSE VERSUS PRASUGREL(RESET TRIAL)
Authors: Gennaro Sardella, Simone Calcagno, Carlotta De Carlo, Mauro Pennacchi, Filippo Placentino, Rocco Stio, Massimo Mancone, Luigi Lucisano, Emanuele Canali, Francesco Fedele
Journal: Journal of the American College of Cardiology (2012)
14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and progenitor cells
Authors: Jing Jiang, Joanna Balcerek, Krasimira Rozenova, Ying Cheng, Alexey Bersenev, Chao Wu, Yiwen Song, Wei Tong
Journal: Journal of Clinical Investigation (2012)

Hematopoietic stem and progenitor cell (HSPC) functions are governed by intricate signaling networks. The tyrosine kinase JAK2 plays an essential role in cytokine signaling during hematopoiesis. The adaptor protein LNK is a critical determinant of this process through its inhibitory interaction with JAK2, thereby limiting HSPC self-renewal. LNK deficiency promotes myeloproliferative neoplasm (MPN) development in mice, and LNK loss-of-function mutations are found in human MPNs, emphasizing its pivotal role in normal and malignant HSPCs. Here, we report the identification of 14-3-3 proteins as LNK binding partners. 14-3-3 interfered with the LNK-JAK2 interaction, thereby alleviating LNK inhibition of JAK2 signaling and cell proliferation. Binding of 14-3-3 required 2 previously unappreciated serine phosphorylation sites in LNK, and we found that their phosphorylation is mediated by glycogen synthase kinase 3 and PKA kinases. Mutations of these residues abrogated the interaction and augmented the growth inhibitory function of LNK. Conversely, forced 14-3-3 binding constrained LNK function. Furthermore, interaction with 14-3-3 sequestered LNK in the cytoplasm away from the plasma membrane-proximal JAK2. Importantly, bone marrow transplantation studies revealed an essential role for 14-3-3 in HSPC reconstitution that can be partially mitigated by LNK deficiency. We believe that, together, this work implicates 14-3-3 proteins as novel and positive HSPC regulators by impinging on the LNK/JAK2 pathway.
Interaction between airway calibre and exhaled NO: Impact on asthma control assessment
Authors: Isabelle Etienne, Alain Michils, Sébastien Michiels, Alain Van Muylem
Journal: European Respiratory Journal (2013)

Background  : Exhaled nitric oxide (FENO) was shown to reflect asthma control change over time (Michils  et al.  ERJ 2008). However, FENO accuracy varies considerably between patients.   Aim : to assess what features may affect FENO ability to reflect asthma control focusing on airway calibre which interferes with FENO.   Methods : Post hoc analysis including 116 asthma patients seen at least 5 times in the out patient asthma clinic. At each visit, FENO and FEV1 were measured; asthma control was assessed by the asthma control questionnaire (ACQ). The individual correlation coefficient r between FENO changes and ACQ score changes over two consecutive visits was computed. Based on r, “concordant” (r>0.7, n=30) and “discordant” (r   Results : FENO, FEV1, and ACQ did not influence concordance, whereas ICS (p=0.015), and, more strikingly, BV (adjusted odds ratio = 4.7 [2.1-10.7], p   Discussion : It is shown that a positive relationship between FENO and FEV1 (BV=1) reduces the ability of FENO to reflect asthma control. This suggests that, in “discordant” patients, airway inflammation and reduction in airway calibre occur in the same lung compartment.   Conclusion : All together, our results suggest that clinicians might have to take into account airway calibre when interpreting FENO changes in asthma patients.
Attitudes About Mandated Coverage of Birth Control Medication and Other Health Benefits in a US National Sample
Authors: Michelle H. Moniz, Matthew M. Davis, Tammy Chang
Journal: JAMA (2014)

Attitudes About Mandated Coverage of Birth Control Medication and Other Health Benefits in a US National SampleAccess to contraception improves maternal and child health. 1 The Patient Protection and Affordable Care Act (ACA) requires most private health insurance plans to cover contraception without a shared patient cost to improve access.However, debate continues about applying the contraception coverage mandate to public corporations that object on religious grounds 2,3 ; the US Supreme Court is reviewing the ACA's contraceptive coverage requirement.We assessed attitudes about mandated coverage of birth control medications.Methods | A cross-sectional survey was administered in November 2013.The survey used the online Knowl-edgePanel (GfK Custom Research North America), a national panel established through probability sampling of the civilian, noninstitutionalized US population (aged ≥18 years).Respondents were asked, "Do you think that all health plans in the United States should be required to include coverage for the following services: birth control medications, preventive services like mammograms and colonoscopies, recommended vaccinations, preventive screening tests for diabetes and high cholesterol, mental health care, and dental/tooth care including dental screenings and tooth problems?"Possible responses included yes, no, uncertain, and refused to answer.The response rate was determined using RR1 of the American Association for Public Opinion Research.Descriptive statistics were calculated for all items.χ 2 Analyses and logistic regression were performed to assess associations between support for birth control medication coverage and demographic factors, applying poststratificaa Statistically different (P < .001)from birth control medications and services in 1 sample test of proportion.b Statistically different (P = .01)from birth control medications and services in 1 sample test of proportion.
Coffee Drinking and Cutaneous Melanoma Risk in the NIH-AARP Diet and Health Study
Authors: Erikka Loftfield, Neal D. Freedman, Barry I. Graubard, Albert R. Hollenbeck, Fatma M. Shebl, Susan T. Mayne, Rashmi Sinha
Journal: JNCI Journal of the National Cancer Institute (2015)

Background:Cutaneous melanoma is the fifth most common cancer in the United States. Modifiable risk factors, with the exception of exposure to ultraviolet radiation (UVR), are poorly understood. Coffee contains numerous bioactive compounds and may be associated inversely with melanoma. However, previous epidemiological evidence is limited.
Clinical evaluation of QuantiFERON TB-2G test for immunocompromised patients
Authors: Y. Kobashi, K. Mouri, Y. Obase, M. Fukuda, N. Miyashita, M. Oka
Journal: European Respiratory Journal (2007)

The usefulness of the tuberculin skin test (TST) and the QuantiFERON TB-2G (QFT-TB) test were compared in immunocompromised patients. The subjects consisted of 252 immunocompromised patients who were clinically suspected of tuberculosis (TB) infection between April 2005 and December 2006. Regarding the underlying diseases, 74 subjects had malignant diseases, 72 were undergoing immunosuppressive treatment, 52 had diabetes mellitus, 50 had chronic renal failure and four had HIV infection. While the positive rate of the QFT-TB test for the diagnosis of TB infection (TB disease or latent TB infection) was 78.1%, that of TST for TB infection was 50.0%. The QFT-TB test was significantly better than TST. However, 32 (13%) patients had an indeterminate QFT-TB result. Indeterminate findings were significantly more frequent in patients receiving immunosuppressive treatment (28%), especially with lymphocytopaenia in the peripheral blood, than in those who had other underlying diseases. While TST-positive and QFT-TB test-negative results were recognised in immunocompromised patients with bacille Calmette–Guérin vaccination or nontuberculous mycobacterial disease, TST-negative and QFT-TB test-positive results were recognised in immunocompromised patients with a past history of TB infection. It was concluded that the QuantiFERON TB-2G test is a more useful diagnostic method for tuberculosis infection than tuberculin skin test for immunocompromised patients suspected of tuberculosis disease. However, because the results of the QuantiFERON TB-2G test show an indeterminate response for patients receiving immunosuppressive treatment, especially for those with lymphocytopaenia due to severe underlying diseases, care must be taken in the interpretation of the QuantiFERON TB-2G test for these patients.