tbuckley/cabot-search huggingface dataset:
p53 Expression in rheumatoid and psoriatic arthritis synovial tissue and association with joint damage
Authors: G Salvador
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Overexpression and functional mutations of p53 have been found in the synovial tissue (ST) of patients with rheumatoid arthritis (RA), but their clinical significance remains unclear. <b>Objective:</b> To analyse p53 expression in the ST of patients with RA and psoriatic arthritis (PsA) and its association with joint damage. <b>Methods:</b> Synovial biopsy specimens were obtained by arthroscopy in 45 patients (27 RA, 18 PsA). Radiographs of hands, feet, and the joint undergoing arthroscopy were obtained to evaluate the presence of erosive disease. Synovial cell populations were analysed using CD4, CD8, CD138, CD20, and CD68 monoclonal antibodies (mAbs). The p53 protein was determined by immunohistology using DO7 mAb in 34 patients (18 RA, 16 PsA). In 11 patients with early RA, the association between p53 and 1 year progression of radiographic damage was analysed using the Larsen-Scott method. <b>Results:</b> The p53 protein was detected in 16/18 (89%) patients with RA and in 9/16 (56%) patients with PsA, but its expression in RA was significantly higher than in PsA. In RA, p53 expression was significantly associated with erosive disease, and its scores were higher in patients with radiological progression. CD68 expression was also associated with erosions and radiological progression in RA. No association was found between either p53 or CD68 and erosive disease in PsA. <b>Conclusions:</b> These results suggest that p53 ST overexpression and association with joint damage is characteristic of RA rather than PsA, and that p53 ST expression might be a prognostic marker of joint damage in RA.
How should we define health?
Authors: M. Huber, J. A. Knottnerus, L. Green, H. v. d. Horst, A. R. Jadad, D. Kromhout, B. Leonard, K. Lorig, M. I. Loureiro, J. W. M. v. d. Meer, P. Schnabel, R. Smith, C. v. Weel, H. Smid
Journal: BMJ (2011)

The WHO definition of health as complete wellbeing is no longer fit for purpose given the rise of chronic disease. <b>Machteld Huber and colleagues </b>propose changing the emphasis towards the ability to adapt and self manage in the face of social, physical, and emotional challenges
Radiation Sensitivity of Human Carcinoma Cells Transfected with Small Interfering RNA Targeted against Cyclooxygenase-2
Authors: Sanjeewani T. Palayoor, Moly J. Arayankalayil, Azadeh Shoaibi, C. Norman Coleman
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Cyclooxygenase-2 (COX-2) is considered a potential target for cancer therapy, because COX-2 levels are elevated in the majority of human tumors compared with the normal tissues. COX-2 inhibitors inhibit tumor growth and enhance radiation response in vitro as well as in vivo. However, the precise role of COX-2 in radiation response is not clear. The purpose of the present study was to investigate the in vitro radiosensitivity of tumor cells as a function of COX-2 expression. Experimental Design and Results: PC3 and HeLa cells express COX-2 protein constitutively. We silenced the COX-2 gene in these cells using small interfering RNA (siRNA). Transfection of PC3 cells with 100 nmol/L siRNA targeted against COX-2 resulted in reduction of COX-2 protein by 75% and inhibition of arachidonic acid–induced prostaglandin E2 synthesis by ∼50% compared with the vehicle control. In HeLa cells, 100 nmol/L COX-2 siRNA inhibited COX-2 protein expression by 80%. Cell cycle analysis showed that transfection with COX-2 siRNA did not alter the cell cycle distribution. Radiosensitivity was determined by clonogenic cell survival assay. There was no significant difference in the radiosensitivity of cells in which COX-2 was silenced compared with the cells transfected vehicle or with negative control siRNAs (enhancement ratio = 1.1). Conclusions: These data indicate that the in vitro radiosensitivity of tumor cells is minimally dependent on the cellular COX-2 status. Given that a number of potential mechanisms are attributed to COX-2 inhibitors for radiosensitization, specific intervention of COX-2 by RNA interference could help elucidate the precise role of COX-2 in cancer therapy and to optimize strategies for COX-2 inhibition.
Hydrogen ion secretion by the collecting duct as a determinant of the urine to blood PCO2 gradient in alkaline urine.
Authors: T D DuBose
Journal: Journal of Clinical Investigation (1982)

Several theories have been advanced to explain the elevation in urinary PCO2 during bicarbonate loading and include: (a) H+ secretion, (b) countercurrent system for CO2, (c) the "ampholyte" properties of bicarbonate, and (d) mixing of urine of disparate bicarbonate and butter concentrations. In this study microelectrodes were used to measure in situ and equilibrium pH (pHis and pHeq) and PCO2 in control and bicarbonate loaded rats before and after infusion of carbonic anhydrase. The disequilibrium pH method (pHdq = pHis - pHeq) was used to demonstrate H+ secretion. Control rats excreting an acid urine (pH = 6.04 +/- 0.06) failed to display a significant disequilibrium pH at the base (BCD), or tip (TCD) of the papillary collecting duct. Urine pH (7.54 +/- 0.12), and urine to blood (U-B) PCO2 increased significantly during NaHCO3 loading while PCO2 at the BCD and TCD also increased (95 +/- 4 and 122 +/- 4). Furthermore, an acid disequilibrium pH was present at both the BCD and TCD (-0.42 +/- 0.04 and -0.36 +/- 0.03) and was obliterated by carbonic anhydrase. Comparison of the PCO2 in the BCD or TCD with the adjacent vasa recta revealed similar values (r = 0.97). It is concluded that H+ secretion by the collecting duct into bicarbonate containing fluid with delayed dehydration of H2CO3, is the most likely determinant of the U-B PCO2 in alkaline urine. Similar values for PCO2 in the collecting duct and the adjacent vasa recta suggests trapping of CO2 in the medullary countercurrent system. The rise in PCO2 occurs both along the collecting duct and after exit from the papilla.
Metastatic Sites As Predictors of Outcome in Renal Cell Carcinoma (Rcc) Patients (Pts) Treated with First-Line Sunitinib (Su) or Sorafenib (So)
Authors: P. Grassi, E. Verzoni, I. Testa, L. Porcu, R. Iacovelli, E. Garanzini, G. Bregni, F.G.M. De Braud, G. Procopio
Journal: Annals of Oncology (2014)
Extracellular ATP Is a Danger Signal Activating P2X<sub>7</sub> Receptor in Lung Inflammation and Fibrosis
Authors: Nicolas Riteau, Pamela Gasse, Louis Fauconnier, Aurélie Gombault, Marion Couegnat, Lizette Fick, Jean Kanellopoulos, Valérie F. J. Quesniaux, Sylvain Marchand-Adam, Bruno Crestani, Bernhard Ryffel, Isabelle Couillin
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Pulmonary fibrosis is a devastating as yet untreatable disease. We previously investigated the endogenous mediators released on lung injury and showed that uric acid is a danger signal activating Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in lung inflammation and fibrosis (Gasse et al., Am J Respir Crit Care Med 2009;179:903-913).Here we address the role of extracellular adenosine triphosphate (eATP) in pulmonary inflammation and fibrosis.ATP was quantified in bronchoalveolar lavage fluid (BALF) of control subjects and patients with idiopathic pulmonary fibrosis. The contribution of eATP as a danger signal was assessed in a murine model of lung fibrosis induced by airway-administered bleomycin (BLM), an intercalating agent that causes DNA strand breaks.Fibrotic patients have elevated ATP content in BALF in comparison with control individuals. In mice, we report an early increase in eATP levels in BALF on BLM administration. Modulation of eATP levels with the ATP-degrading enzyme apyrase greatly reduced BLM-induced inflammatory cell recruitment, lung IL-1β, and tissue inhibitor of metalloproteinase (TIMP)-1 production, while administration of ATP-γS, a stable ATP derivative, enhanced inflammation. P2X(7) receptor-deficient mice presented dramatically reduced lung inflammation, with reduced fibrosis markers such as lung collagen content and matrix-remodeling proteins TIMP-1 and matrix metalloproteinase-9. The acute inflammation depends on a functional pannexin-1 hemichannel protein. In vitro, ATP is released by pulmonary epithelial cells on BLM-induced stress and this is partly dependent on the presence of functional P2X(7) receptor and pannexin-1 hemichannel.ATP released from BLM-injured lung cells constitutes a major endogenous danger signal that engages the P2X(7) receptor/pannexin-1 axis, leading to IL-1β maturation and lung fibrosis.
Statistical and Practical Considerations for Clinical Evaluation of Predictive Biomarkers
Authors: M.-Y. C. Polley, B. Freidlin, E. L. Korn, B. A. Conley, J. S. Abrams, L. M. McShane
Journal: JNCI Journal of the National Cancer Institute (2013)

Predictive biomarkers to guide therapy for cancer patients are a cornerstone of precision medicine. Discussed herein are considerations regarding the design and interpretation of such predictive biomarker studies. These considerations are important for both planning and interpreting prospective studies and for using specimens collected from completed randomized clinical trials. Specific issues addressed are differentiation between qualitative and quantitative predictive effects, challenges due to sample size requirements for predictive biomarker assessment, and consideration of additional factors relevant to clinical utility assessment, such as toxicity and cost of new therapies as well as costs and potential morbidities associated with routine use of biomarker-based tests.
IgE Cross-reactivity between the Cysteine Proteases Der p 1 and Act c 1, the Major Allergens from House Dust Mites and Kiwifruit
Authors: B. Merima, C. Radauer, C. Ebner, D. Allwardth, W.R. Thomas, A. Mari, A. Knulst, O. Scheiner, H. Breiteneder
Journal: Journal of Allergy and Clinical Immunology (2006)
What Causes Sudden Death in Heart Failure?
Authors: Gordon F. Tomaselli, Douglas P. Zipes
Journal: Circulation Research (2004)

Patients with heart failure experience a number of changes in the electrical function of the heart that predispose to potentially lethal cardiac arrhythmias. Action potential prolongation, the result of functional downregulation of K currents, and aberrant Ca2+ handling is a recurrent theme. Significant alterations in conduction and activation of a number of initially adaptive but ultimately maladaptive signaling cascades contribute to the generation of a highly arrhythmogenic substrate. We review the changes in active and passive membrane properties, neurohumoral signaling, and genetic determinants that predispose to sudden arrhythmic death in patients with heart failure and highlight the critical unanswered questions that are ripe for future investigation.
Reduced inspiratory flow attenuates IL‐8 release and MAPK activation of lung overstretch
Authors: M. Kotani, T. Kotani, Z. Li, R. Silbajoris, C.A. Piantadosi, Y-C.T. Huang
Journal: European Respiratory Journal (2004)

Lung overstretch involves mechanical factors, including large tidal volumes (VT), which induce inflammatory responses. The current authors hypothesised that inspiratory flow contributes to ventilator-induced inflammation. Buffer-perfused rabbit lungs were ventilated for 2 h with 21%, O2+5%, CO2, positive end-expiratory pressure of 2-3 cmH2O and randomly assigned to either: 1) normal VT (6 mL x kg(-1)) at respiratory rate (RR) 30, inspiration:expiration time ratio (I:E) 1:1, low inspiratory flow 6 mL x kg(-1) x s(-1); 2) large VT (12 mL x kg(-1)) at RR 30, I:E 1:1, high inspiratory flow 12 mL x kg(-1) x s(-1) (HRHF); 3) large VT at RR 15, I:E 1:1, low inspiratory flow 6 mL x kg(-1) x s(-1) (LRLF); or 4) large VT at RR 15, I:E 1:2.3, high inspiratory flow 10 mL x kg(-1) x s(-1) (LRHF). Physiological parameters, tumour necrosis factor (TNF)-alpha, interleukin (IL)-8 and activation of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK)1/2, p38 and stress-activated protein kinase (SAPK)/ c-Jun N-terminal kinase (JNK)) were measured. HRHF increased weight gain, perfusate IL-8 and phosphorylation of ERK1/2, p38 and SAPK/JNK. These responses were absent during LRLF but present during LRHF. Changes in TNF-alpha were small. Tissue IL-8 and phospho-ERK1/2 staining was localised primarily to smooth muscle, adventitia and bronchial epithelium within larger bronchioles and arterioles. These results indicate that mild overstretch of perfused lungs during high inspiratory flow enhances inflammatory signalling by cells in lung regions most affected by strong turbulent airflow.
Endogenous red blood cell membrane fatty acids and sudden cardiac arrest
Authors: Rozenn N. Lemaitre, Irena B. King, Nona Sotoodehnia, Robert H. Knopp, Dariush Mozaffarian, Barbara McKnight, Thomas D. Rea, Kenneth Rice, Yechiel Friedlander, Thomas S. Lumley, Trivellore E. Raghunathan, Michael K. Copass, David S. Siscovick
Journal: Metabolism (2010)
Pulmonary and cutaneous nodules in an immunocompromised patient
Authors: P. J. Vlachostergios, S. Karamagkiolis, K. Karamitsos
Journal: Thorax (2011)

Figure 1 Papules and nodules on hands (A) and soles (B).(C) Chest CT scan showing multiple bilateral solid pulmonary nodules with peribronchovascular distribution and a cavitating nodule in the left lower lobe.(D) Abdominal CT scan showing multiple hepatic ring-enhancing lesions.
Weight-Loss Intervention by Telephone: Lessons Learned
Authors: Judith Wylie-Rosett
Journal: Diabetes Care (2014)

The dramatic rise in the prevalence of obesity and type 2 diabetes is clearly a strain on health care systems globally (1). Recently published guidelines on obesity management indicate that a sustained weight loss of 3–5% is likely to result in clinically meaningful reductions in triglycerides, blood glucose, and A1C (2). However, the 2013 Obesity Guidelines noted achieving more weight loss (∼10%) will also reduce blood pressure, improve LDL cholesterol and HDL cholesterol, and reduce the need for medications required to control cardiometabolic risk (2). The Look AHEAD (Actions for Health in Diabetes) trial provides evidence, specific to diabetes, that an intensive lifestyle intervention can achieve a 5–10% weight loss and can improve sleep apnea quality-of-life indices, achieve cardiometabolic biomarker improvements, and reduce need for medications (3–6). These benefits are emphasized in the 2013 Obesity Guidelines (2). Challenges to providing an intensive intervention in primary care practice setting, as required to achieve the suggested outcomes, include the lack of staffing and resources required to adhere to the schedule for the intensive follow-up. In this regard, telephone contact, along with other technologies that have the potential to provide frequent contact with a lower staff and patient burden, is …
Upsurge in T-Wave Alternans and Nonalternating Repolarization Instability Precedes Spontaneous Initiation of Ventricular Tachyarrhythmias in Humans
Authors: Vladimir Shusterman, Anna Goldberg, Barry London
Journal: Circulation (2006)

Analysis of repolarization instability, manifested by T-wave alternans (TWA), has proved useful for arrhythmia risk assessment. However, temporal relations between TWA and the spontaneous initiation of ventricular tachyarrhythmias (VTA) in humans are unknown. We examined continuous dynamics of repolarization in Holter electrocardiograms with spontaneous sustained (>30 seconds) VTA.Ambulatory electrocardiograms from 42 patients (79% with ischemic heart disease; left ventricular ejection fraction, 37+/-15%) were digitized, and the lead with the highest magnitude of the T wave was selected for analysis. TWA was examined by the modified moving average and intrabeat average analyses. To examine non-TWA (longer-period) oscillations in the repolarization segment, spectral energy of oscillations of consecutive T-wave amplitudes was calculated with the use of the short-time Fourier transform. Heart rate variability was assessed with the Fourier transform as well. TWA increased before the onset of VTA and reached a peak value of 23.6+/-11.7 microV 10 minutes before the event (P=0.0007). Spectral power of the oscillations of consecutive T-wave amplitudes increased nonuniformly, with the greatest increase in the respiratory range (2.6 microV2; P=0.005). In the TWA range, the change was smaller but highly pronounced relative to the 60- to 120-minute level (65%; P=0.003). The low-frequency and high-frequency heart rate variability power declined before the arrhythmia (P=0.04 and P=0.06, respectively).The magnitude of repolarization instability, manifested by TWA and beat-to-beat oscillations of T-wave amplitudes at other frequencies, increased before the onset of VTA. Tracking of these dynamics can facilitate timely detection of high-risk periods and may be useful for initiation of preventive treatments.
Increased ILC2s in the Eosinophilic Nasal Polyp Endotype Are Associated with Corticosteroid Responsiveness
Authors: Hannah H. Walford, Sean Lund, Rachel Baum, Andrew A. White, Christopher Bergeron, Jacob Husseman, Kelly Bethel, David R. Scott, Marina Miller, David H. Broide, Taylor Doherty
Journal: Journal of Allergy and Clinical Immunology (2015)
Insulin-like Growth Factor–Binding Protein-2 Is a Target for the Immunomodulation of Breast Cancer
Authors: Kyong Hwa Park, Ekram Gad, Vivian Goodell, Yushe Dang, Thayer Wild, Doreen Higgins, Patty Fintak, Jennifer Childs, Corazon dela Rosa, Mary L. Disis
Journal: Cancer Research (2008)

Breast cancer is immunogenic and well suited to treatment via immunomodulation. The disease is often treated to remission and time to relapse is generally measured in years in many cases. Immune-based therapeutics, such as cancer vaccines, may be able to affect the clinical progression of micrometastatic disease. Immune targets must be identified that have the potential to inhibit tumor growth. Insulin-like growth factor-binding protein-2 (IGFBP-2) has direct effects on breast cancer proliferation via stimulation of critical signaling pathways. We questioned whether IGFBP-2 was an immune target in breast cancer. IGFBP-2-specific IgG antibody immunity was preferentially detected in breast cancer patients compared with controls (P = 0.0008). To evaluate for the presence of T-cell immunity, we identified potential pan-HLA-DR binding epitopes derived from IGFBP-2 and tested the peptides for immunogenicity. The majority of epitopes elicited peptide-specific T cells in both patients and controls and had high sequence homology to bacterial pathogens. IGFBP-2 peptide-specific T cells could respond to naturally processed and presented IGFBP-2 protein, indicating that these peptides were native epitopes of IGFBP-2. Finally, both immunization with IGFBP-2 peptides as well as adoptive transfer of IGFBP-2-competent T cells mediated an antitumor effect in a transgenic mouse model of breast cancer. This is the first report of IGFBP-2 as a human tumor antigen that may be a functional therapeutic target in breast cancer.
Oncogenic Property of Acrogranin in Human Uterine Leiomyosarcoma: Direct Evidence of Genetic Contribution in <i>In vivo</i> Tumorigenesis
Authors: Noriomi Matsumura, Masaki Mandai, Masanori Miyanishi, Ken Fukuhara, Tsukasa Baba, Toshihiro Higuchi, Masatoshi Kariya, Kenji Takakura, Shingo Fujii
Journal: Clinical Cancer Research (2006)

To identify potential oncogenes that contribute to the development of uterine leiomyosarcoma, we conducted a cDNA microarray analysis between normal uterine smooth muscle and uterine leiomyosarcoma. We found that acrogranin (also named PCDGF or progranulin) is overexpressed in uterine leiomyosarcoma. With immunohistochemical staining of 12 leiomyosarcoma cases, we verified acrogranin expression in tumor cells. Furthermore, the intensity of acrogranin expression correlated with high histologic grade and poor prognosis. To directly analyze the oncogenic properties of acrogranin, we established an immortalized uterine smooth muscle cell line by transfection of human telomerase reverse transcriptase into primary culture. This cell line retained the original characteristics of uterine smooth muscle cells, including spindle-shaped extension as well as expression of vimentin, estrogen receptor alpha, progesterone receptor, and alpha smooth muscle actin. Transfection of acrogranin into the immortalized uterine smooth muscle cells resulted in colony formation in soft agar, but the diameter of the colonies did not exceed 100 mum. Transfection of both acrogranin and SV40 early region (SV40ER) into the immortalized uterine smooth muscle cells resulted in an increased number of colonies and increased colony size in soft agar versus transfection of SV40ER alone. We show that only immortalized uterine smooth muscle cells expressing both acrogranin and SV40ER are capable of tumor formation in nude mice. Thus, acrogranin is overexpressed in uterine leiomyosarcoma cells, particularly in high-grade cases, and forced expression of acrogranin in immortalized uterine smooth muscle cells contributes to malignant transformation, which suggest that acrogranin plays an important role in the pathogenesis of uterine leiomyosarcoma.
Bakery work, atopy and the incidence of self-reported hay fever and rhinitis
Authors: J Brisman, B Jarvholm
Journal: European Respiratory Journal (1999)

The aims of this study were to estimate the risk to bakers of developing hay fever and rhinitis, to assess the modifying effect of atopy and to estimate the occurrence of job change due to nasal symptoms. A retrospective cohort study was performed among bakers trained in Swedish trade schools from 1961 to 1989 (n=2,923). School control subjects (n=1,258) comprised students in other programmes in the trade schools and population controls (n=1,258) were randomly selected from the general population. A questionnaire on hay fever, rhinitis, the year of onset of these diseases, change of work due to nasal symptoms and work history was mailed to all participants. The atopic state of the responders was assessed by questions on allergic diseases in childhood and among next of kin. Incidence rates for hay fever and other rhinitis were calculated. The relative risk (RR) for hay fever when working as a baker compared with all control subjects combined was increased in males (RR=1.9, 95% confidence interval (CI) 1.2-2.9). The RR for rhinitis in male bakers compared with combined control subjects was 2.8 (95% CI 2.3-3.4) and for female bakers 2.0 (1.6-2.7). Of the bakers, 6.1% had changed job due to nasal symptoms, significantly more than the controls. A history of respiratory atopy increased the incidence rates of hay fever and rhinitis, with a synergistic effect between atopy and bakery work in males. In conclusion, Swedish bakers, mainly working in the 1970s and 1980s, had an approximately doubled risk of developing rhinitis. Male bakers also had an increased risk for hay fever. There was a synergistic effect of bakery work and atopy such as a family history of hay fever. Bakers also changed job due to nasal symptoms more often than control subjects.