tbuckley/cabot-search huggingface dataset:
Hypothermia during reperfusion limits 'no-reflow' injury in a rabbit model of acute myocardial infarction
Authors: S Hale
Journal: Cardiovascular Research (2003)

Reflow following coronary artery occlusion is an important predictor of clinical outcome. This study tests the effects of regional hypothermia, initiated late during ischemia and maintained for 2 h of reperfusion, on the no-reflow phenomenon.Anesthetized, open-chest New Zealand White rabbits received 30 min of coronary artery occlusion and 3 h reperfusion. Regional myocardial hypothermia (H, n=14), starting 10 min before reperfusion and continuing for 2 h of reperfusion, was compared with normothermia (N, n=14). Regional myocardial blood flow (microspheres) was measured during occlusion and at the end of reperfusion. The anatomic zone of no-reflow (thioflavin S in vivo injection) and infarct size were measured in the ischemic risk region at the end of the study.Myocardial temperature in H rabbits was decreased by 5.0+/-0.4 degrees C from baseline (37.1+/-0.2 degrees C) and remained about 32 degrees C during the cooling phase, returning to 36.0+/-0.3 degrees C at 3 h. N hearts remained within 0.2 degrees C of baseline (37.3+/-0.1 degrees C) throughout. Both groups were equally ischemic during occlusion, but at the end of reperfusion reflow to the previously ischemic zone was significantly higher in H, 77+/-5% of normal blood flow versus 36+/-4% in N (P=0.0001). The zone of anatomic no-reflow was significantly smaller in H, 11+/-3% of the ischemic risk zone versus 37+/-3% in N (P=0.0001), and was proportionally smaller when represented as a percent of the necrotic zone 36+/-6% compared with 75+/-5% in N. Infarct size, expressed as a percent of the ischemic risk zone was significantly smaller in H vs. N hearts (27+/-4 and 51+/-5%, P=0.0000).This study shows that hypothermic therapy initiated late during ischemia and continuing for several hours of reperfusion significantly improves reflow and reduces macroscopic zones of no-reflow and necrosis in this model. The improvement in reflow was greater than would be expected in the H group compared with N, based on the extent of necrosis. As reflow is a predictor of outcome, this intervention may have clinical implications.
Diabetes as a Determinant of Mortality in Cystic Fibrosis
Authors: Parinya Chamnan, Brian S.F. Shine, Charles S. Haworth, Diana Bilton, Amanda I. Adler
Journal: Diabetes Care (2009)

OBJECTIVE Diabetes is increasingly common in cystic fibrosis, but little information describing its influence on mortality exists. Using national U.K. data, in this study we document diabetes-specific mortality rates, estimate the impact of diabetes on survival, and estimate population-attributable fractions. RESEARCH DESIGN AND METHODS This retrospective cohort study identified 8,029 individuals aged 0–65 years from the U.K. Cystic Fibrosis Registry (1996–2005). A total of 5,892 patients were included in analyses of mortality rates, and 4,234 were included in analyses of risk factors. We calculated age-adjusted mortality rates using Poisson regression, standardized mortality ratios using the population of England and Wales, and relative risks using proportional hazards modeling. RESULTS During 17,672 person-years of follow-up, 393 subjects died. The age-adjusted mortality rate was 1.8 per 100 person-years (95% CI 1.6–2.0). The age-adjusted mortality rates per 100 person-years were 2.0 (1.8–2.4) in female subjects and 1.6 (1.4–1.9) in male subjects, and 4.2 (3.4–5.1) in individuals with diabetes vs. 1.5 (1.3–1.7) in those without diabetes. Independent risk factors for death included diabetes (hazard ratio 1.31 [95% CI 1.03–1.67], female sex (1.71 [1.36–2.14]) plus poorer pulmonary function, lower BMI, Burkholderia cepacia infection, absence of Staphylococcus aureus infection, allergic bronchopulmonary aspergillosis, liver disease, prior organ transplantation, and corticosteroid use. CONCLUSIONS Individuals with cystic fibrosis die earlier if they have diabetes, which, if delayed or better treated, might reasonably extend survival; this hypothesis merits testing.
Antiangiogenic Properties of Fibstatin, an Extracellular FGF-2–Binding Polypeptide
Authors: Carine Bossard, Loic Van den Berghe, Henrik Laurell, Caroline Castano, Martine Cerutti, Anne-Catherine Prats, Hervé Prats
Journal: Cancer Research (2004)

Abstract By using the two-hybrid system with basic fibroblast growth factor (FGF-2) as bait, we isolated and characterized fibstatin, an endogenous Mr 29,000 human basement membrane-derived inhibitor of angiogenesis and tumor growth. Fibstatin, a fragment containing the type III domains 12–14 of fibronectin, was produced as a recombinant protein and was shown to inhibit the proliferation, migration, and differentiation of endothelial cells in vitro. Antiangiogenic activity of fibstatin was confirmed in a Matrigel angiogenesis assay in vivo, and electrotransfer of the fibstatin gene into muscle tissue resulted in reduced B16F10 tumor growth. Taken together, these results suggest that fibstatin could act as a powerful molecule for antiangiogenic therapy.
Developmental regulation of Foxp3 expression during ontogeny
Authors: Jason D. Fontenot, James L. Dooley, Andrew G. Farr, Alexander Y. Rudensky
Journal: The Journal of Experimental Medicine (2005)

Thymectomy of neonatal mice can result in the development of autoimmune pathology. It has been proposed that thymic output of regulatory T (T reg) cells is delayed during ontogeny and that the development of autoimmune disease in neonatally thymectomized mice is caused by the escape of self-reactive T cells before thymectomy without accompanying T reg cells. However, the kinetics of T reg cell production within the thymus during ontogeny has not been assessed. We demonstrate that the development of Foxp3-expressing T reg cells is substantially delayed relative to nonregulatory thymocytes during ontogeny. Based on our data, we speculate that induction of Foxp3 in developing thymocytes and, thus, commitment to the T reg cell lineage is facilitated by a signal largely associated with the thymic medulla.
Working towards healthy air in dwellings in Europe
Authors: M. Franchi, P. Carrer, D. Kotzias, E. M. A. L. Rameckers, O. Seppänen, J. E. M. H. Van Bronswijk, G. Viegi, J. A. Gilder, E. Valovirta
Journal: Allergy (2006)

Poor indoor air quality has been implicated in the increase in allergic and respiratory diseases seen in industrialized countries in recent decades. Although air pollution in the workplace is well studied, much less is known about the consequences of poor air quality in homes. In an attempt to halt or slow down the increase in allergic and respiratory diseases, the European Federation of Allergy and Airways Diseases Patients Associations (EFA) carried out the EU‐funded project entitled ‘Towards Healthy Air in Dwellings in Europe’ (THADE). The aims were to: compile an overview of evidence‐based data about exposure to indoor air pollution and its health effects, particularly in relation to allergies, asthma and other respiratory diseases such as chronic obstructive pulmonary disease; review cost‐effective measures and technology to improve indoor air quality; review legislation and guidelines on indoor air pollution; produce maps of pollutants in dwellings; and recommend an integrated strategy that defines appropriate indoor air quality policies for implementation in Europe. This paper summarizes the information about air quality in dwellings and indoor environment‐related diseases collected by expert consultants within the framework of THADE and terminates with recommendations for actions aimed at improving air quality in homes. The results of this project confirmed that air pollution in dwellings is a relevant health problem. It is a complex problem that must be addressed at European and international levels, and it involves the medical profession, scientific societies, patients’ organizations, lawmakers, architects and the building industry. The complete THADE report is available at http://www.efanet.org/activities/documents/THADEReport.pdf .
Successful surgical repair of congenital total cleft sternum with partial ectopia cordis.
Authors: A Aytac, A Saylam
Journal: Thorax (1976)

Total bifid sternum with or without ectopia cordis is a rare congenital anomaly which is treated successfully in a limited number of cases. Several methods of correction have been described using tissue grafts (cartilage, bone), inert artificial prostheses (acrylic plaques, marlex mesh), and techniques to approximate the sternal bands by relaxation of costal cartilages. In our case the method described by Verska was used to approximate the bifid sternal bands. The successful result in our patient proves the efficiency of this technique.
Chronic diarrhoea-all in the bowel?
Authors: S Gupta, C J Tibbs, M J G Farthing, R C G Pollok
Journal: Journal of the Royal Society of Medicine (2007)

Chronic diarrhoea is a common presenting symptom of patients attending gastroenterology clinics. When routine tests fail to reveal a cause for the diarrhoea, rarer causes need to be excluded. We report such a case where a diagnosis of medullary thyroid carcinoma (MTC) was eventually made. The patient underwent radical surgery with amelioration of her symptom. Diarrhoea is rarely the presenting symptom of MTC but it should be considered in the differential diagnosis of chronic diarrhoea. Measurement of serum calcitonin should be included in the investigation of difficult chronic diarrhoea.
DDB2 Suppresses Epithelial-to-Mesenchymal Transition in Colon Cancer
Authors: Nilotpal Roy, Prashant V. Bommi, Uppoor G. Bhat, Shaumick Bhattacharjee, Indira Elangovan, Jing Li, Krushna C. Patra, Dragana Kopanja, Adam Blunier, Richard Benya, Srilata Bagchi, Pradip Raychaudhuri
Journal: Cancer Research (2013)

Colon cancer is one of the deadliest cancers worldwide because of its metastasis to other essential organs. Metastasis of colon cancer involves a complex set of events, including epithelial-to-mesenchymal transition (EMT) that increases invasiveness of the tumor cells. Here, we show that the xeroderma pigmentosum group E (XPE) gene product, damaged DNA-binding protein (DDB)-2, is downregulated in high-grade colon cancers, and it plays a dominant role in the suppression of EMT of the colon cancer cells. Depletion of DDB2 promotes mesenchymal phenotype, whereas expression of DDB2 promotes epithelial phenotype. DDB2 constitutively represses genes that are the key activators of EMT, indicating that DDB2 is a master regulator of EMT of the colon cancer cells. Moreover, we observed evidence that DDB2 functions as a barrier for EMT induced by hypoxia and TGF-β. Also, we provide evidence that DDB2 inhibits metastasis of colon cancer. The results presented here identify a transcriptional regulatory pathway of DDB2 that is directly linked to the mechanisms that suppress metastasis of colon cancer.
A Novel Carbohydrate-Based Therapeutic GCS-100 Overcomes Bortezomib Resistance and Enhances Dexamethasone-Induced Apoptosis in Multiple Myeloma Cells
Authors: Dharminder Chauhan, Guilan Li, Klaus Podar, Teru Hideshima, Paola Neri, Deli He, Nicholas Mitsiades, Paul Richardson, Yan Chang, Joanne Schindler, Bradley Carver, Kenneth C. Anderson
Journal: Cancer Research (2005)

Abstract Human multiple myeloma is a presently incurable hematologic malignancy, and novel biologically based therapies are urgently needed. GCS-100 is a polysaccharide derived from citrus pectin in clinical development for the treatment of cancer. Here we show that GCS-100 induces apoptosis in various multiple myeloma cell lines, including those resistant to dexamethasone, melphalan, or doxorubicin. Examination of purified patient multiple myeloma cells showed similar results. Specifically, GCS-100 decreases viability of bortezomib/PS-341–resistant multiple myeloma patient cells. Importantly, GCS-100 inhibits multiple myeloma cell growth induced by adhesion to bone marrow stromal cells; overcome the growth advantage conferred by antiapoptotic protein Bcl-2, heat shock protein-27, and nuclear factor-κB; and blocks vascular endothelial growth factor–induced migration of multiple myeloma cells. GCS-100–induced apoptosis is associated with activation of caspase-8 and caspase-3 followed by proteolytic cleavage of poly(ADP-ribose) polymerase enzyme. Combined with dexamethasone, GCS-100 induces additive anti-multiple myeloma cytotoxicity associated with mitochondrial apoptotic signaling via release of cytochrome c and Smac followed by activation of caspase-3. Moreover, GCS-100 + dexamethasone–induced apoptosis in multiple myeloma cells is accompanied by a marked inhibition of an antiapoptotic protein Galectin-3, without significant alteration in Bcl-2 expression. Collectively, these findings provide the framework for clinical evaluation of GCS-100, either alone or in combination with dexamethasone, to inhibit tumor growth, overcome drug resistance, and improve outcome for patients with this universally fatal hematologic malignancy.
Melanomas disable DCs
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

T cells need to be activated by dendritic cells (DCs) before they will attack a tumor. Sumimoto et al. (page 1651) now show that a common skin cancer mutation interferes with this pathway, thus helping the tumor to evade the body's immune defenses.

Activating point mutations in the serine-threonine kinase BRAF are found in 66% of all malignant melanomas. The resulting activation of BRAF-ERK-MAPK signaling—the primary pathway involved in growth factor–induced proliferation of melanocytes—immortalizes the cells.

One BRAF mutation (BRAFV600E), according to Sumimoto and colleagues, also prompts human tumor cells to produce vascular endothelial growth factor, interleukin (IL)-6 and IL-10, all of which inhibit the production of proinflammatory cytokines by dendritic cells (DCs).

Disabling DCs, and thereby preventing their activation of tumor-specific T cells, is a popular tumor cell trick. Indeed, activation of the transcription factor STAT3—common among hematopoietic and epithelial cancers—triggers the production of a similar array of DC-inhibiting cytokines. In that model, blocking STAT3 in tumor-bearing mice resulted in T cell attack on the tumor. Whether blocking BRAF will have the same reinvigorating effect on melanoma-specific T cells awaits the development of an animal model.

Interfering with BRAF signaling might enhance immune-activating antitumor therapies, such as DC immunization or T cell immunotherapy, as activation of the cells induced by these approaches might otherwise be blunted by the tumor's suppressive output.
Benefit of Clopidogrel in Patients With Acute Coronary Syndromes Without ST-Segment Elevation in Various Risk Groups
Authors: Andrzej Budaj, Salim Yusuf, Shamir R. Mehta, Keith A.A. Fox, Gianni Tognoni, Feng Zhao, Susan Chrolavicius, David Hunt, Matyas Keltai, Maria Grazia Franzosi
Journal: Circulation (2002)

The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial demonstrated that clopidogrel, given early and continued long term, was superior to placebo in patients with non-ST-elevation acute coronary syndromes receiving aspirin. The purpose of the present analysis was to estimate the treatment effect Zof clopidogrel in patients who were stratified according to their risk of future cardiovascular events.Patients (n=12 562) who presented within 24 hours after the onset of symptoms were randomized to receive clopidogrel (300 mg followed by 75 mg daily) or placebo in addition to aspirin for 3 to 12 months. Treatment effect was analyzed in various risk groups according to the Thrombolysis in Myocardial Infarction (TIMI) risk score. The TIMI risk model was validated in the CURE population (C statistic, 0.634). The primary composite outcome of cardiovascular death, myocardial infarction, or stroke increased proportionally with increasing risk according to the TIMI risk score. The impact of clopidogrel versus placebo on the rate of the primary outcome was as follows: low-risk group (TIMI score 0 to 2), 4.1% versus 5.7% (relative risk [RR], 0.71; 95% confidence interval [CI], 0.52 to 0.97; P< 0.04), intermediate-risk group (TIMI score 3 to 4), 9.8% versus 11.4% (RR, 0.85; 95% CI, 0.74 to 0.98; P<0.03), and high-risk group (TIMI score 5 to 7), 15.9% versus 20.7% (RR, 0.73; 95% CI, 0.60 to 0.90; P<0.004). There was no evidence of statistical heterogeneity among the groups.The benefit of clopidogrel demonstrated in the CURE trial is consistent in low-, intermediate-, and high-risk patients with acute coronary syndromes (as stratified by TIMI risk score), thus supporting its use in all patients with documented non-ST elevation acute coronary syndromes.
Assessment of respiratory muscle strength in the intensive care unit
Authors: J Moxham, J Goldstone
Journal: European Respiratory Journal (1994)

The measurement of respiratory muscle strength in the intensive care unit (ICU) is potentially useful for the prediction of weaning outcome. An easy and accurate measure would also allow investigation of respiratory muscle weakness in critically ill patients. At present, there is no satisfactory method of strength measurement in the intensive care unit. Vital capacity is a nonspecific, volitional and relatively insensitive measure of strength. True maximum respiratory pressures are difficult to achieve and, in stable patients, results vary greatly both over time and between observers. For these reasons, there are few good data of respiratory muscle strength in the intensive care unit. Of the new techniques being developed, magnetic stimulation of the phrenic nerves, combined with the measurement of transdiaphragmatic, oesophageal, or endotracheal tube pressure, offers the greatest promise.
Evidence for longer survival of patients with pleural mesothelioma without asbestos exposure.
Authors: M R Law, F G Ward, M E Hodson, B E Heard
Journal: Thorax (1983)

In a group of 23 patients with histologically confirmed malignant mesothelioma of the pleura who could not recall exposure to asbestos dust, survival was significantly longer than in a group of 83 patients with known exposure. Asbestos bodies were found by a quantitative method significantly less frequently in the unexposed than in the exposed group. The longer survival of patients without known exposure could not be correlated with any significant difference in the histological cell types of the tumours from those of exposed patients. In the 83 patients with known exposure survival did not relate to duration of exposure. Consequently, although the tumours of patients unable to recall exposure may be caused by unrecognised environmental contamination with asbestos dust, the longer survival of these patients would suggest a different aetiology.
The effect of cyclic-AMP on the regulation of c-myc expression in T lymphoma cells.
Authors: D A Albert
Journal: Journal of Clinical Investigation (1995)

Myc is implicated in the control of growth in a variety of cell types. I investigated c-myc gene expression in several lymphoid cell lines to determine the response to cyclic AMP. Cyclic AMP causes a precipitous decline in c-myc message concentration that precedes G1 cell cycle arrest in wild type S49 cells but not in KIN- cells that lack cAMP dependent PKA activity. In wild-type S49 cells washout of cyclic AMP restores c-myc message levels within 2 h but does not relieve the G1 arrest until 10 h later. Transcription runoff studies demonstrate inhibition of both transcriptional initiation and prolongation of initiated transcripts. However, the degree of inhibition is insufficient to explain the absence of detectable myc message suggesting that the predominant effect of cyclic AMP is to destabilize the c-myc message. In contrast to wild-type cells, the "Deathless" mutant S49 cell line is viable when arrested in G1 by exposure to cyclic AMP and has preserved c-myc expression. Thus, in S49 cells down regulation of c-myc expression appears to be associated with loss of viability rather than G1 cell cycle arrest. Interestingly, CEM human T lymphoma cells do not arrest in G1 phase when exposed to cyclic AMP in spite of losing detectable c-myc gene expression. This suggests that in some T lymphoma cells c-myc gene expression may not be necessary for cell cycle progression and proliferation.
Loss of nuclear pro–IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma
Authors: Clara Curiel-Lewandrowski, Hisato Yamasaki, Chuan Ping Si, Xiaoyi Jin, Yujun Zhang, Jillian Richmond, Marina Tuzova, Kevin Wilson, Beth Sullivan, David Jones, Nataliya Ryzhenko, Frederick Little, Thomas S. Kupper, David M. Center, William W. Cruikshank
Journal: Journal of Clinical Investigation (2011)

Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin lymphomas that affect the skin. The pathogenesis of these conditions is poorly understood. For example, the signaling mechanisms contributing to the dysregulated growth of the neoplastic T cells are not well defined. Here, we demonstrate that loss of nuclear localization of pro-IL-16 facilitates CTCL cell proliferation by causing a decrease in expression of the cyclin dependent-kinase inhibitor p27Kip1. The decrease in p27Kip1 expression was directly attributable to an increase in expression of S-phase kinase-associated protein 2 (Skp2). Regulation of Skp2 is in part attributed to the nuclear presence of the scaffold protein pro-IL-16. T cells isolated from 11 patients with advanced CTCL, but not those from healthy controls or patients with T cell acute lymphocytic leukemia (T-ALL), demonstrated reduction in nuclear pro-IL-16 levels. Sequence analysis identified the presence of mutations in the 5' end of the PDZ1 region of pro-IL-16, a domain required for association of pro-IL-16 with the nuclear chaperone HSC70 (also known as HSPA8). HSC70 knockdown led to loss of nuclear translocation by pro-IL-16 and subsequent increases in Skp2 levels and decreases in p27Kip1 levels, which ultimately enhanced T cell proliferation. Thus, our data indicate that advanced CTCL cell growth is facilitated, at least in part, by mutations in the scaffold protein pro-IL-16, which directly regulates Skp2 synthesis.