tbuckley/cabot-search huggingface dataset:
CIB1 Regulates Endothelial Cells and Ischemia-Induced Pathological and Adaptive Angiogenesis
Authors: Mohamed A. Zayed, Weiping Yuan, Tina M. Leisner, Dan Chalothorn, Andrew W. McFadden, Michael D. Schaller, M. Elizabeth Hartnett, James E. Faber, Leslie V. Parise
Journal: Circulation Research (2007)

Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. CIB1 (calcium- and integrin-binding protein), a 22-kDa EF-hand-containing protein, modulates the activity of p21-activated kinase 1 in fibroblasts. Because p21-activated kinase 1 also contributes to endothelial cell function, we hypothesized that CIB1 may have a role in angiogenesis. We found that endothelial cells depleted of CIB1 by either short hairpin RNA or homologous recombination have reduced migration, proliferation, and tubule formation. Moreover, loss of CIB1 in these cells decreases p21-activated kinase 1 activation, downstream extracellular signal-regulated kinase 1/2 activation, and matrix metalloproteinase 2 expression, all of which are known to contribute to angiogenesis. Consistent with these findings, tissues derived from CIB1-deficient (CIB1-/-) mice have reduced growth factor-induced microvessel sprouting in ex vivo organ cultures and in vivo Matrigel plugs. Furthermore, in response to ischemia, CIB1-/- mice demonstrate decreased pathological retinal and adaptive hindlimb angiogenesis. Ischemic CIB1-/- hindlimbs also demonstrate increased tissue damage and significantly reduced p21-activated kinase 1 activation. These data therefore reveal a critical role for CIB1 in ischemia-induced pathological and adaptive angiogenesis.
Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus
Authors: L. L. Ritterhouse, S. R. Crowe, T. B. Niewold, D. L. Kamen, S. R. Macwana, V. C. Roberts, A. B. Dedeke, J. B. Harley, R. H. Scofield, J. M. Guthridge, J. A. James
Journal: Annals of the Rheumatic Diseases (2011)

Vitamin D deficiency is widespread and has been associated with many chronic diseases, including autoimmune disorders. A study was undertaken to explore the impact of low vitamin D levels on autoantibody production in healthy individuals, as well as B cell hyperactivity and interferon α (IFNα) activity in patients with systemic lupus erythematosus (SLE).
Copper and Iron Disorders of the Brain
Authors: Erik Madsen, Jonathan D. Gitlin
Journal: Annual Review of Neuroscience (2007)

Copper and iron are transition elements essential for life. These metals are required to maintain the brain's biochemistry such that deficiency or excess of either copper or iron results in central nervous system disease. This review focuses on the inherited disorders in humans that directly affect copper or iron homeostasis in the brain. Elucidation of the molecular genetic basis of these rare disorders has provided insight into the mechanisms of copper and iron acquisition, trafficking, storage, and excretion in the brain. This knowledge permits a greater understanding of copper and iron roles in neurobiology and neurologic disease and may allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.
Liquid-Based Cytology: Evaluation of Effectiveness, Cost-Effectiveness, and Application to Present Practice
Authors: J. Thomas Cox
Journal: Journal of the National Comprehensive Cancer Network (2004)

This article reviews the data available as of 2004 on the effectiveness and cost-effectiveness of cervical screening with the two available cytologic methods, the conventional Papanicolaou (Pap; CP) smear and liquid-based cytology (LBC), and discusses the application of LBC to current practice. The majority of LBC studies are on the ThinPrep Pap Test (CYTYC, Boxsborough, MA) and the remainder are on SurePath (TriPath, Burlington, NC), which was previously known as AutoCyte Prep. LBC identified more low-grade squamous intraepithelial lesion (LSIL) Pap test results compared with paired conventional cytology in 17 of 21 ThinPrep and 9 of 12 SurePath “split-sample” studies considered to fulfill the criteria for inclusion in the British NHS Health Technology Assessment (HTA) evaluation of cervical cytology. In four of the six recent ThinPrep and one of two SurePath split-sample studies, more high-grade squamous intraepithelial lesion-positive (HSIL+) results were identified by LBC than by CP. All 15 “direct-to vial studies” meeting HTA criteria reported more LSIL+ results for LBC compared with CP, and all eight of the direct-to-vial studies reporting HSIL+ results separately showed increased detection of high-grade cytology interpretations. Fifteen studies met the criteria for evaluating sensitivity and specificity. Aggregate sensitivity for the CP was 71.5% and for LBC was 80.1%. Indirect comparisons of the two LBC methods did not detect a difference in sensitivity, and a meta-analysis of the six studies comparing specificity between CP and LBC found no difference. Other capabilities of LBC are improved specimen adequacy and the ability to do ancillary testing out of the liquid-based vial. In cost-effective analyses based on models of disease natural history and/or the clinical effectiveness of each screening modality, screening with CP was always dominated by screening with LBC. Primary cervical screening guidelines issued by the American Cancer Society in 2002 recommend repeating the cytology biannually if liquid-based and annually if conventional. The gain in sensitivity, apparent cost-effectiveness, and advantage of having a representative specimen for ancillary testing, support the use of LBC.
The metabolic bone disease of primary sclerosing cholangitis
Authors: Eileen J. Hay, Keith D. Lindor, Russell H. Wiesner, Rolland E. Dickson, Ruud A. F. Krom, Nicholas F. Larusso
Journal: Hepatology (1991)

The incidence and severity of osteopenic bone disease in primary sclerosing cholangitis is poorly defined. Clinical, biochemical and radiographic assessment and bone mineral density measurements of the lumbar spine were carried out in two groups of patients. Group 1 consisted of 30 patients with advanced primary sclerosing cholangitis; group 2 consisted of 18 patients with newly diagnosed primary sclerosing cholangitis. Only one patient had bone pain. All patients were normocalcemic; two had elevated serum parathormone levels. Fourteen patients (47%) from group 1 but no patients from group 2 had low serum 25-hydroxyvitamin D levels. Mean bone mineral density was significantly reduced in group 1 patients (0.97 +/- 0.04 gm/cm2) compared with age-matched and sex-matched controls (1.25 +/- 0.01 gm/cm2, p less than 0.0001), and in 15 patients (50%) bone mineral density was below the fracture threshold (0.98 gm/cm2). The bone mineral density in group 2 was not significantly different from controls, and no patient was below the fracture threshold. In neither group did bone mineral density correlate with serum bilirubin, 25-hydroxyvitamin D, fecal fat excretion, previous drug therapy or the presence of chronic ulcerative colitis. Histomorphometrical examination of bone from four group 1 patients showed increased bone resorption, reduced bone formation, moderate-to-severe osteopenia and no osteomalacia. In conclusion, severe osteopenic bone disease is common in advanced primary sclerosing cholangitis and, like that seen in other cholestatis diseases, is consistent with osteoporosis.
Using a Pericentromeric Interspersed Repeat to Recapitulate the Phylogeny and Expansion of Human Centromeric Segmental Duplications
Authors: J. E. Horvath, C. L. Gulden, J. A. Bailey, C. Yohn, John Douglas Mcpherson, A. Prescott, B. A. Roe, P. J. De Jong, M. Ventura, D. Misceo, N. Archidiacono, S. Zhao, S. Schwartz, M. Rocchi, E. E. Eichler
Journal: Molecular Biology and Evolution (2003)

Despite considerable advances in sequencing of the human genome over the past few years, the organization and evolution of human pericentromeric regions have been difficult to resolve. This is due, in part, to the presence of large, complex blocks of duplicated genomic sequence at the boundary between centromeric satellite and unique euchromatic DNA. Here, we report the identification and characterization of an approximately 49-kb repeat sequence that exists in more than 40 copies within the human genome. This repeat is specific to highly duplicated pericentromeric regions with multiple copies distributed in an interspersed fashion among a subset of human chromosomes. Using this interspersed repeat (termed PIR4) as a marker of pericentromeric DNA, we recovered and sequence-tagged 3 Mb of pericentromeric DNA from a variety of human chromosomes as well as nonhuman primate genomes. A global evolutionary reconstruction of the dispersal of PIR4 sequence and analysis of flanking sequence supports a model in which pericentromeric duplications initiated before the separation of the great ape species (>12 MYA). Further, analyses of this duplication and associated flanking duplications narrow the major burst of pericentromeric duplication activity to a time just before the divergence of the African great ape and human species (5 to 7 MYA). These recent duplication exchange events substantially restructured the pericentromeric regions of hominoid chromosomes and created an architecture where large blocks of sequence are shared among nonhomologous chromosomes. This report provides the first global view of the series of historical events that have reshaped human pericentromeric regions over recent evolutionary time.
Vascular Disease in a Dish
Authors: Sanjay Sinha
Journal: Circulation (2012)

T he emerging field of stem cell medicine offers unprece- dented opportunities, among which the ability to model genetic diseases in vitro is one of the most exciting.In particular, disease modeling using stem cells promises to deliver a deeper understanding of disease mechanisms and to provide a test bed for novel therapies within a relatively short timeframe.The seminal discovery by Shinya Yamanaka only 6 years ago that somatic adult cells, such as fibroblasts taken from the skin, could be reprogrammed into cells that look and behave remarkably like embryonic stem cells 1 has greatly accelerated progress toward these goals.These induced pluripotent stem cells (iPSCs), in common with their embryonic counterparts, possess the ability to self-replicate indefinitely yet also have the capacity to differentiate into almost any somatic cell type.Importantly, if derived from patients with overt disease, iPSCs will possess both the disease-causing mutation as well as the permissive genetic background that in many cases is required for full expression of the disease phenotype.In this issue of Circulation, Qyang and colleagues 2 use this technology to increase our understanding of the vascular smooth muscle cell (SMC) pathology in supravalvular aortic stenosis (SVAS) and Williams-Beuren Syndrome (WBS)-conditions associated with reduced elastin expression and incorporation into the vascular wall.
Time course and pattern of COPD exacerbation onset
Authors: Shawn D Aaron, Gavin C Donaldson, George A Whitmore, John R Hurst, Tim Ramsay, Jadwiga A Wedzicha
Journal: Thorax (2011)

<h3>Background</h3> The natural history and time course of the onset of exacerbation events of chronic obstructive pulmonary disease (COPD) is incompletely understood. <h3>Methods</h3> A prospective cohort of 212 patients with COPD was monitored using daily symptom diaries for a median of 2.8 years to characterise the time course of COPD exacerbation onset. Decision rules based on weighted self-reported symptoms were used to define opening and closing of exacerbation events. Event time intervals were analysed and logistic regression was used to determine the effects of patient covariates on exacerbation events. <h3>Results</h3> Patients recorded 4439 episodes of worsening respiratory symptoms from baseline; 2444 (55%) events resolved spontaneously and 1995 (45%) resulted in a COPD exacerbation. In 1115 of the 1995 COPD exacerbations (56%) the onset was sudden and the exacerbation threshold was crossed on the same day symptoms began. In contrast, 44% of exacerbations were characterised by gradual onset of symptoms (median duration from symptom onset to exacerbation 4 days). Patients who experienced sudden onset exacerbations had greater mean daily symptom scores (7.86 vs 6.55 points, p&lt;0.001), greater peak symptom scores (10.7 vs 10.2 points, p=0.003), earlier peak symptoms (4.5 vs 8.0 days, p&lt;0.001) and shorter median recovery times back to baseline health status (11 vs 13 days, p&lt;0.001). Multivariable analysis showed that gradual onset exacerbations were statistically associated with a longer duration of exacerbation recovery (OR 1.28, 95% CI 1.06 to 1.54, p=0.010). <h3>Conclusions</h3> COPD exacerbations exhibit two distinct patterns—sudden and gradual onset. Sudden onset exacerbations are associated with increased respiratory symptoms but shorter exacerbation recovery times.
Magnetic Resonance Imaging for the Detection, Localisation, and Characterisation of Prostate Cancer: Recommendations from a European Consensus Meeting
Authors: Louise Dickinson, Hashim U. Ahmed, Clare Allen, Jelle O. Barentsz, Brendan Carey, Jurgen J. Futterer, Stijn W. Heijmink, Peter J. Hoskin, Alex Kirkham, Anwar R. Padhani, Raj Persad, Philippe Puech, Shonit Punwani, Aslam S. Sohaib, Bertrand Tombal, Arnauld Villers, Jan van der Meulen, Mark Emberton
Journal: European Urology (2010)
Epidemiology of hepatitis B virus infection in India.
Authors: B N Tandon, S K Acharya, A Tandon
Journal: Gut (1996)

The average estimated carrier rate of hepatitis B virus (HBV) in India is 4%, with a total pool of approximately 36 million carriers. Wide variations in social, economic, and health factors in different regions may explain variations in carrier rates from one part of the country to another. Professional blood donors constitute the major high risk group for HBV infection in India, with a hepatitis B surface antigen positivity rate of 14%. Blood transfusions represent the most important route of HBV transmission among adults. However, most of India9s carrier pool is established in early childhood, predominantly by horizontal spread due to crowded living conditions and poor hygiene. Acute and subacute liver failure are common complications of viral hepatitis in India and HBV is reckoned to be the aetiological agent in 42% and 45% of adult cases, respectively. HBV is reported to be responsible for 70% of cases of chronic hepatitis and 80% of cases of cirrhosis of the liver. About 60% of patients with hepatocellular carcinoma are HBV marker positive. Small numbers of patients have been reported to be infected with the pre-core mutant virus but none with the S mutant. Coinfection with hepatitis C virus or hepatitis delta virus is comparatively uncommon. In conclusion, hepatitis B is a major public health problem in India and will continue to be until appropriate nationwide vaccination programmes and other control measures are established.
Tumor Apoptotic Bodies Inhibit CTL Responses and Antitumor Immunity via Membrane-Bound Transforming Growth Factor-β1 Inducing CD8+ T-Cell Anergy and CD4+ Tr1 Cell Responses
Authors: Yufeng Xie, Ou Bai, Jinying Yuan, Rajni Chibbar, Karen Slattery, Yangdou Wei, Yulin Deng, Jim Xiang
Journal: Cancer Research (2009)

Tumor cell apoptosis induced by radiation therapy results in apoptotic tumor cells and apparition of membrane blebs termed apoptotic bodies (APB). The immune responses induced by apoptotic tumor cells have been extensively studied. However, the role of APB in modulation of tumor immune responses is elusive. In this study, we induced apoptosis in 90% ovabumin-expressing EG7 tumor cells by in vitro irradiation (9,000 rad) of tumor cells with a subsequent cell culture for 9 hours. APB purified from irradiation-induced apoptotic EG7 cell culture supernatant by differential ultracentrifugation were vesicles with 50 to 90 nm in diameter and expressed apoptosis-specific Annexin V, 14-3-3, and Histone H3. We then investigated its potential modulation in DC(OVA)-induced T-cell responses and antitumor immunity. We found that EG7-derived APB were tolerogenic and capable of suppressing DC(OVA)-stimulated CD8+ CTL responses and antitumor immunity via its induction of CD8+ T-cell anergy and type 1 regulatory CD4+ T-cell responses. Analysis of apoptotic tumor cells and APB revealed the expression of membrane-bound transforming growth factor (TGF)-beta1 associated with irradiation-induced apoptosis formation, which is a result from activation of transcriptional factor NF-AT specific for TGF-beta1 promoters. Our data further elucidate that it is the membrane-bound TGF-beta1 expression on APB that contributes to its in vitro antiproliferative effect as shown by using neutralizing TGF-beta1-specific antibody. Administration of anti-TGF-beta1 antibody in vivo also blocked APB-mediated immune suppression of CD8+ CTL responses and antitumor immunity. Therefore, our study may have great impact in designing a combined radiation therapy with immunotherapy of cancer.
Overexpression of Hemopexin in the Diabetic Eye
Authors: Cristina Hernández, Marta Garcia-Ramírez, Rafael Simó
Journal: Diabetes Care (2013)

OBJECTIVE Hemopexin is a well-recognized permeability factor in the kidney, but its potential role in blood-retinal barrier (BRB) breakdown has not been explored. The main aims of this study were as follows: 1) to determine hemopexin expression in the retina and its content in the vitreous fluid from diabetic patients with diabetic macular edema (DME) and nondiabetic patients, 2) to evaluate the effect of hemopexin on BRB permeability, and 3) to determine whether dexamethasone prevents an eventual hemopexin-induced hyperpermeability. RESEARCH DESIGN AND METHODS Biological material included 1) retinas from 10 diabetic donors with nonproliferative retinopathy and from 10 nondiabetic donors and 2) vitreous fluid from 14 patients with DME and 14 nondiabetic patients. Hemopexin and hemopexin receptor mRNA levels were measured by quantitative RT-PCR and hemopexin concentrations by ELISA. The effect of hemopexin on permeability in culture was evaluated in human retinal pigment epithelial (ARPE)-19 cells and bovine retinal endothelial cells. The experiments were repeated in the presence of hemopexin-neutralizing antibodies and dexamethasone. RESULTS A higher expression of hemopexin was detected in the retinal pigment epithelium (RPE) from diabetic patients in comparison with nondiabetic control subjects. Intravitreal hemopexin concentration was higher in patients with DME than in nondiabetic subjects. Hemopexin significantly increased permeability in ARPE-19 cells, which was prevented by both hemopexin-neutralizing antibodies and dexamethasone. CONCLUSIONS Hemopexin is overexpressed in the RPE of diabetic patients with DME and induces the breakdown of RPE cells in vitro. Dexamethasone was able to prevent hemopexin-induced hyperpermeability. Our results suggest that hemopexin can be considered a new pathogenic candidate for DME.
Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study
Authors: Adriana Balduzzi, Maria Grazia Valsecchi, Cornelio Uderzo, Paola De Lorenzo, Thomas Klingebiel, Christina Peters, Jan Stary, Maria S Felice, Edina Magyarosy, Valentino Conter, Alfred Reiter, Chiara Messina, Helmut Gadner, Martin Schrappe
Journal: The Lancet (2005)
Gastrointestinal bleeding: don't overlook the role of the pancreas
Authors: R. Spiller
Journal: Gut (2005)

Background and aim: In acute liver failure (ALF), the brain is exposed to high levels of ammonia.Human studies defining the clinical significance of ammonia in ALF are lacking.This prospective study evaluated the relationship of arterial ammonia levels at admission to complications and survival among patients with ALF.Methods: Eighty consecutive ALF patients admitted from March 2001 to December 2003 were followed up until death or complete recovery.All had arterial ammonia estimation at admission (enzymatic method).Logistic regression analysis was performed to identify independent predictors of mortality.Results: Forty two (52.5%)patients died.Non-survivors had significantly higher median ammonia levels than survivors (174.7 v 105.0 mmol/l; p,0.001).An arterial ammonia level of > 124 mmol/l was found to predict mortality with 78.6% sensitivity and 76.3% specificity, and had 77.5% diagnostic accuracy.Patients with higher ammonia levels also developed more complications, including deeper encephalopathy (p = 0.055), cerebral oedema (p = 0.020), need for ventilation (p,0.001), and seizures (p = 0.006).Logistic regression analysis showed that pH, presence of cerebral oedema, and arterial ammonia at admission were independent predictors of mortality (odds ratios 6.6, 12.6, and 10.9, respectively).Incorporating these variables, a score predicting mortality risk at admission was derived: 2.53 + 2.91 ammonia + 2.41 oedema + 1.40 pH, where ammonia is scored as 0 (if ,124 mmol/l) or 1 (if >124 mmol/l); oedema is scored as 0 (absent) or 1(present); and pH is scored as 1 (if (7.40) or 0 (if .7.40).Levels of partial pressure of ammonia were equally correlated with outcome.Conclusion: Arterial ammonia at presentation is predictive of outcome and can be used for risk stratification.Ammonia lowering therapies in patients with ALF should be evaluated.
Phase III Trial of Bevacizumab in Combination With Gemcitabine and Erlotinib in Patients With Metastatic Pancreatic Cancer
Authors: Eric Van Cutsem, Walter L. Vervenne, Jaafar Bennouna, Yves Humblet, Sharlene Gill, Jean-Luc Van Laethem, Chris Verslype, Werner Scheithauer, Aijing Shang, Jan Cosaert, Malcolm J. Moore
Journal: Journal of Clinical Oncology (2009)

Treatment with gemcitabine provides modest benefits in patients with metastatic pancreatic cancer. The addition of erlotinib to gemcitabine shows a small but significant improvement in overall survival (OS) versus gemcitabine alone. Phase II results for bevacizumab plus gemcitabine provided the rationale for a phase III trial of gemcitabine-erlotinib plus bevacizumab or placebo.Patients with metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine (1,000 mg/m(2)/week), erlotinib (100 mg/day), and bevacizumab (5 mg/kg every 2 weeks) or gemcitabine, erlotinib, and placebo in this double-blind, phase III trial. Primary end point was OS; secondary end points included progression-free survival (PFS), disease control rate, and safety.A total of 301 patients were randomly assigned to the placebo group and 306 to the bevacizumab group. Median OS was 7.1 and 6.0 months in the bevacizumab and placebo arms, respectively (hazard ratio [HR], 0.89; 95% CI, 0.74 to 1.07; P = .2087); this difference was not statistically significant. Adding bevacizumab to gemcitabine-erlotinib significantly improved PFS (HR, 0.73; 95% CI, 0.61 to 0.86; P = .0002). Treatment with bevacizumab plus gemcitabine-erlotinib was well tolerated: safety data did not differ from previously described safety profiles for individual drugs.The primary objective was not met. The addition of bevacizumab to gemcitabine-erlotinib did not lead to a statistically significant improvement in OS in patients with metastatic pancreatic cancer. PFS, however, was significantly longer in the bevacizumab group compared with placebo. No unexpected safety events were observed from adding bevacizumab to gemcitabine-erlotinib.