tbuckley/cabot-search huggingface dataset:
The “No-Reflow” Phenomenon after Temporary Coronary Occlusion in the Dog
Authors: Robert A. Kloner, Charles E. Ganote, Robert B. Jennings
Journal: Journal of Clinical Investigation (1974)

The role of microvascular damage in the genesis of the “no-reflow” phenomenon was investigated in the left ventricular myocardium of dogs subjected to temporary occlusions of a major coronary artery for 40 and 90 min. Intravenous carbon black or thioflavin S (a fluorescent vital stain for endothelium) were used to demonstrate the distribution of coronary arterial flow in control and damaged myocardium. These tracers were injected simultaneously with release of the coronary occlusion or after 5 or 20 min of reflow of coronary arterial blood. After 40 min of ischemia plus arterial reperfusion, usually the tracers were evenly distributed throughout the damaged tissue at each time of reperfusion. On the other hand, when reflow was allowed after 90 min of ischemia, portions of the inner half of damaged myocardium were not penetrated by the tracers. Electron microscopic study of this poorly perfused tissue revealed severe capillary damage; endothelial cells with large intraluminal protrusions and decreased pinocytic vesicles were common. Also, occasional intraluminal fibrin thrombi were noted, as well as extravascular fibrin deposits and erythrocytes. Myocardial cells were swollen in both poorly perfused and well-perfused irreversibly injured tissue. Contraction bands and mitochondrial Ca2+ accumulation were prominent features of irreversible injury with reflow at 40 min but were not noted after 90 min of ischemia in areas with poor perfusion. These results suggest that 40 min of ischemia were tolerated by the capillary bed of the dog heart without serious capillary damage or perfusion defects, but that 90 min of ischemic injury was associated with the “no-reflow” phenomenon, i.e., failure to achieve uniform reperfusion. This failure of reflow was associated with extensive capillary damage and myocardial cell swelling. Death of severely ischemic myocardial cells in this model occurs before the onset of capillary damage and the no-reflow phenomenon.
Estimation of Population Divergence Times from Non-Overlapping Genomic Sequences: Examples from Dogs and Wolves
Authors: P. Skoglund, A. Gotherstrom, M. Jakobsson
Journal: Molecular Biology and Evolution (2010)

Despite recent technological advances in DNA sequencing, incomplete coverage remains to be an issue in population genomics, in particular for studies that include ancient samples. Here, we describe an approach to estimate population divergence times for non-overlapping sequence data that is based on probabilities of different genealogical topologies under a structured coalescent model. We show that the approach can be adapted to accommodate common problems such as sequencing errors and postmortem nucleotide misincorporations, and we use simulations to investigate biases involved with estimating genealogical topologies from empirical data. The approach relies on three reference genomes and should be particularly useful for future analysis of genomic data that comprise of nonoverlapping sets of sequences, potentially from different points in time. We applied the method to shotgun sequence data from an ancient wolf together with extant dogs and wolves and found striking resemblance to previously described fine-scale population structure among dog breeds. When comparing modern dogs to four geographically distinct wolves, we find that the divergence time between dogs and an Indian wolf is smallest, followed by the divergence times to a Chinese wolf and a Spanish wolf, and a relatively long divergence time to an Alaskan wolf, suggesting that the origin of modern dogs is somewhere in Eurasia, potentially southern Asia. We find that less than two-thirds of all loci in the boxer and poodle genomes are more similar to each other than to a modern gray wolf and that--assuming complete isolation without gene flow--the divergence time between gray wolves and modern European dogs extends to 3,500 generations before the present, corresponding to approximately 10,000 years ago (95% confidence interval [CI]: 9,000-13,000). We explicitly study the effect of gene flow between dogs and wolves on our estimates and show that a low rate of gene flow is compatible with an even earlier domestication date ∼30,000 years ago (95% CI: 15,000-90,000). This observation is in agreement with recent archaeological findings and indicates that human behavior necessary for domestication of wild animals could have appeared much earlier than the development of agriculture.
Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury
Authors: X. Han, S. Gilbert, K. Groschwitz, S. Hogan, I. Jurickova, B. Trapnell, C. Samson, J. Gully
Journal: Gut (2010)

<h3>Background</h3> Administration of granulocyte-macrophage colony stimulating factor (GM-CSF) relieves symptoms in Crohn9s disease (CD). It has been reported that reduced GM-CSF bioactivity is associated with more aggressive ileal behaviour and that GM-CSF-null mice exhibit ileal barrier dysfunction and develop a transmural ileitis following exposure to non-steroidal anti-inflammatory drugs (NSAIDs). STAT5 signalling is central to GM-CSF action. It was therefore hypothesised that GM-CSF signalling in non-haematopoietic cells is required for ileal homeostasis. <h3>Methods</h3> Bone marrow (BM) chimeras were generated by reconstituting irradiated GM-CSF receptor (<i>gm-csfr</i>) β chain or GM-CSF (<i>gm-csf</i>) deficient mice with wild type BM (WTBM→GMRKO and WTBM→GMKO). Intestinal barrier function and the response to NSAID-induced ileal injury were examined. Expression of <i>gm-csf</i>, <i>gm-csfr</i> or <i>stat5</i> in Caco-2 and HT-29 intestinal epithelial cell (IEC) lines was knocked down and the effect of GM-CSF signalling on IEC survival and proliferation was determined. <h3>Results</h3> Elevated levels of GM-CSF autoantibodies in ileal CD were found to be associated with dysregulation of IEC survival and proliferation. GM-CSF receptor-deficient mice and WTBM→GMRKO chimeras exhibited ileal hyperpermeability. NSAID exposure induced a transmural ileitis in GM-CSF receptor-deficient mice and WTBM→GMRKO chimeras. Transplantation of wild type BM into GM-CSF-deficient mice prevented NSAID ileal injury and restored ileal barrier function. Ileal crypt IEC proliferation was reduced in WTBM→GMRKO chimeras, while STAT5 activation in ileal IEC following NSAID exposure was abrogated in WTBM→GMRKO chimeras. Following knock down of <i>gm-csf</i>, <i>gm-csfr α</i> or <i>β</i> chain or <i>stat5a/b</i> expression in Caco-2 cells, basal proliferation was suppressed. GM-CSF normalised proliferation of Caco-2 cells exposed to NSAID, which was blocked by <i>stat5a/b</i> RNA interference. <h3>Conclusions</h3> Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury; furthermore, GM-CSF signalling in non-haematopoietic cells regulates ileal epithelial homeostasis via the STAT5 pathway. The therapeutic use of GM-CSF may therefore be beneficial in chronic ileitis associated with CD.
Association Between Fine Particulate Matter and Diabetes Prevalence in the U.S.
Authors: John F. Pearson, Chethan Bachireddy, Sangameswaran Shyamprasad, Allison B. Goldfine, John S. Brownstein
Journal: Diabetes Care (2010)

OBJECTIVE Recent studies have drawn attention to the adverse effects of ambient air pollutants such as particulate matter 2.5 (PM2.5) on human health. We evaluated the association between PM2.5 exposure and diabetes prevalence in the U.S. and explored factors that may influence this relationship. RESEARCH DESIGN AND METHODS The relationship between PM2.5 levels and diagnosed diabetes prevalence in the U.S. was assessed by multivariate regression models at the county level using data obtained from both the Centers for Disease Control and Prevention (CDC) and U.S. Environmental Protection Agency (EPA) for years 2004 and 2005. Covariates including obesity rates, population density, ethnicity, income, education, and health insurance were collected from the U.S. Census Bureau and the CDC. RESULTS Diabetes prevalence increases with increasing PM2.5 concentrations, with a 1% increase in diabetes prevalence seen with a 10 μg/m3 increase in PM2.5 exposure (2004: β = 0.77 [95% CI 0.39–1.25], P &amp;lt; 0.001; 2005: β = 0.81 [0.48–1.07], P &amp;lt; 0.001). This finding was confirmed for each study year in both univariate and multivariate models. The relationship remained consistent and significant when different estimates of PM2.5 exposure were used. Even for counties within guidelines for EPA PM2.5 exposure limits, those with the highest exposure showed a &amp;gt;20% increase in diabetes prevalence compared with that for those with the lowest levels of PM2.5, an association that persisted after controlling for diabetes risk factors. CONCLUSIONS Our results suggest PM2.5 may contribute to increased diabetes prevalence in the adult U.S. population. These findings add to the growing evidence that air pollution is a risk factor for diabetes.
Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity
Authors: Fei Duan, Jorge Duitama, Sahar Al Seesi, Cory M. Ayres, Steven A. Corcelli, Arpita P. Pawashe, Tatiana Blanchard, David McMahon, John Sidney, Alessandro Sette, Brian M. Baker, Ion I. Mandoiu, Pramod K. Srivastava
Journal: The Journal of Experimental Medicine (2014)

The mutational repertoire of cancers creates the neoepitopes that make cancers immunogenic. Here, we introduce two novel tools that identify, with relatively high accuracy, the small proportion of neoepitopes (among the hundreds of potential neoepitopes) that protect the host through an antitumor T cell response. The two tools consist of (a) the numerical difference in NetMHC scores between the mutated sequences and their unmutated counterparts, termed the differential agretopic index, and (b) the conformational stability of the MHC I–peptide interaction. Mechanistically, these tools identify neoepitopes that are mutated to create new anchor residues for MHC binding, and render the overall peptide more rigid. Surprisingly, the protective neoepitopes identified here elicit CD8-dependent immunity, even though their affinity for Kd is orders of magnitude lower than the 500-nM threshold considered reasonable for such interactions. These results greatly expand the universe of target cancer antigens and identify new tools for human cancer immunotherapy.
Early functional disability predicts both all-cause and cardiovascular mortality in people with inflammatory polyarthritis: results from the Norfolk Arthritis Register
Authors: T. M Farragher, M. Lunt, D. K Bunn, A. J Silman, D. P M Symmons
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To investigate the predictive value of early functional disability in patients with inflammatory polyarthritis (IP), for all-cause and cardiovascular disease (CVD) mortality. <b>Methods:</b> 1010 subjects with new-onset IP from the Norfolk Arthritis Register were studied. All were seen at baseline and at 1 year. Health Assessment Questionnaire (HAQ) scores were obtained at both time points. Vital status at 10 years from registration was established through central records. Mortality (all-cause and CVD) per 1000 person-years were calculated by HAQ stratum (HAQ scores &lt;1, 1–2 and ⩾2). The predictive value of HAQ (per unit increase) at the two time points, adjusted for age at onset of symptom, sex and other factors found to predict mortality, was assessed using Cox regression models. The analysis was repeated for those who satisfied the 1987 American College of Rheumatology criteria for rheumatoid arthritis (RA) by 5 years. <b>Results:</b> By 10 years, 171 (16.9%) subjects had died. 89 deaths (52%) were attributed to CVD. Mortality was greatest in the highest HAQ group at both time points. Following adjustment for other predictors, HAQ score at year 1 remained a significant predictor of all-cause mortality (HR 1.46; 95% CI 1.15 to 1.85) and CVD mortality (HR 1.49; 95% CI 1.12 to 1.97). The predictive value of HAQ at year 1 was similar in the RA subgroup. <b>Conclusions:</b> Our data show that at 1 year of follow-up, HAQ score is an important independent predictor of subsequent all-cause and CVD mortalities in people with IP and RA. Baseline HAQ scores are of less value.
Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha (infliximab) in spondyloarthropathy: an open pilot study
Authors: F. Van den Bosch
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To evaluate the efficacy and safety of a loading dose regimen of three intravenous infusions with infliximab in patients with active spondyloarthropathy. <h3>METHODS</h3> A monocentre, open-label pilot study of 21 patients with different subtypes of spondyloarthropathy was conducted. Treatment resistant patients with active disease (fulfilling inclusion criteria) received three infusions of 5 mg/kg infliximab (at weeks 0, 2, and 6). Standard clinical assessments were performed at baseline, and on days 3, 7, and 14, and from then on every two weeks. In patients who fulfilled criteria for ankylosing spondylitis, axial assessment was performed at baseline and on days 14, 42, and 84. <h3>RESULTS</h3> In all global assessments (visual analogue scale of patient global assessment, patient pain assessment, doctor global assessment), erythrocyte sedimentation rate, and C reactive protein, a highly significant decrease could be seen already at day 3 (compared with baseline), which was maintained up to day 84. In patients with peripheral disease (n=18), tender and swollen joint count significantly decreased. In patients with axial disease (n=11), functional and disease activity indices significantly improved. Moreover in eight patients with psoriatic arthritis a significant decrease of the psoriasis area and severity index was observed. The treatment was well tolerated in all patients; no significant adverse events were seen. <h3>CONCLUSION</h3> In this open-label pilot study of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor α in patients with active spondyloarthropathy, there was a fast and significant improvement of axial and peripheral articular manifestations, without major adverse experiences.
Two independent receptors allow selective target lysis by T cell clones.
Authors: H Binz, M Fenner, D Frei, H Wigzell
Journal: The Journal of Experimental Medicine (1983)

Dimethylbenzanthracene-induced P1 sarcoma cells induce P1-specific antibodies in syngeneic DA rats. Antiidiotypic antibodies of specificity DA anti-(DA anti-P1) were induced against the tumor-specific antibodies and used to restimulate P1-primed DA T cells in vitro. Using antiidiotypic antibodies and T cell growth factor, P1-specific cytotoxic DA T cell clones were established by limiting dilution and kept in vitro. Two of these clones acquired during culture periods in addition to the P1 specificity lytic activity towards natural killer (NK) targets YAC-1 or K562. Cold target inhibition experiments showed that the very same cytotoxic T cells kill P1 and NK targets. Antiidiotypic antibodies of specificity DA anti-(DA anti-P1) inhibited cytotoxicity against P1 but not against YAC-1 or K562. We conclude that two independent receptors are located on these double-reactive T cell clones, one that is idiotypic and antigen-specific, and another displaying the binding profile of NK cells.
Induction of human immunoglobulin synthesis and secretion in somatic cell hybrids of mouse myeloma and human B lymphocytes from patients with agammaglobulinemia.
Authors: J F Schwaber, F S Rosen
Journal: The Journal of Experimental Medicine (1978)

Somatic cell hybrid clones were isolated from the fusion of RPC 5,4 mouse myeloma cells and B lymphocytes from three patients with agammaglobulinemia. One patient had X-linked agammaglobulinemia; the remaining two patients had common varied agammaglobulinemia. All three patients had B lymphocytes which fail to secrete immunoglobulin. The hybrid nature of the clones was established by examination of metaphase chromosome spreads. Most of the clones from all three patients expressed surface immunoglobulin of mouse and human parental origin. Clones from two of the patients had fewer cells with surface Ig than hybrids from normal persons, while clones from the third patient had large numbers of surface Ig fluorescent cells. Most of the clones from all three patients synthesized and secreted human and mouse immunoglobulin. As determined by sodium dodecyl sulfate acrylamide gel electrophoresis of radioactively labeled proteins, clones from each of the patients produced human gamma, alpha, and mu-heavy chains. These studies demonstrate the presence of functional structural genes coding for human immunoglobulin heavy chains in B lymphocytes of patients with agammaglobulinemia. Further, they represent induction in the somatic cell hybrids of a gene product not expressed in the parental B lymphocytes.
Mre11-Dependent Degradation of Stalled DNA Replication Forks Is Prevented by BRCA2 and PARP1
Authors: Songmin Ying, Freddie C. Hamdy, Thomas Helleday
Journal: Cancer Research (2012)

PARP inhibitors are currently being used in clinical trials to treat BRCA1- or BRCA2-defective tumors, based on the synthetic lethal interaction between PARP1 and BRCA1/2-mediated homologous recombination (HR). However, the molecular mechanisms that drive this synthetic lethality remain unclear. Here, we show increased levels of Mre11, a key component of MRN (Mre11-Rad50-Nbs1) complex that plays a role in the restart of stalled replication forks and enhanced resection at stalled replication forks in BRCA2-deficient cells. BRCA2-deficient cells also showed hypersensitivity to the Mre11 inhibitor mirin. Interestingly, PARP1 activity was required to protect stalled forks from Mre11-dependent degradation. Resistance to PARP inhibition in BRCA2-mutant cells led to reduced levels of Mre11 foci and also rescued their sensitivity to mirin. Taken together, our findings not only show that Mre11 activity is required for the survival of BRCA2 mutant cells but also elucidate roles for both the BRCA2 and PARP1 proteins in protecting stalled replication forks, which offers insight into the molecular mechanisms of the synthetic lethality between BRCA2 and PARP1.
Acute respiratory failure due to tracheobronchial involvement in Crohn's disease
Authors: C Lamblin, MC Copin, C Billaut, R Marti, V Tacq, O Riviere, B Wallaert
Journal: European Respiratory Journal (1996)

We present a case of tracheobronchial involvement in Crohn's disease, associated with respiratory failure leading to mechanical ventilation. Bronchoscopy revealed small, diffuse, whitish granulations and erythematous mucosa. Histopathology disclosed ulcerative bronchitis and noncaseating tuberculoid granuloma. The patient improved under a 6 week oral corticosteroid treatment followed by inhaled corticotherapy, without relapse of pulmonary symptoms.
Identifying the mesenchymal molecular subtype of glioblastoma using quantitative volumetric analysis of anatomic magnetic resonance images
Authors: Kourosh M. Naeini, Whitney B. Pope, Timothy F. Cloughesy, Robert J. Harris, Albert Lai, Ascia Eskin, Reshmi Chowdhury, Heidi S. Phillips, Phioanh L. Nghiemphu, Yalda Behbahanian, Benjamin M. Ellingson
Journal: Neuro-Oncology (2013)

Subtypes of glioblastoma multiforme (GBM) based on genetic and molecular alterations are thought to cause alterations in anatomic MRI owing to downstream biological changes, such as edema production, blood-brain barrier breakdown, and necrosis. The purpose of the current study was to identify a potential relationship between imaging features and the mesenchymal (MES) GBM subtype, which has the worst patient prognosis.MRIs from 46 patients with histologically confirmed GBM were retrospectively analyzed. The volume of contrast enhancement, regions of central necrosis, and hyperintensity of T2/fluid attenuated inversion recovery (FLAIR) were measured. Additionally, the ratio of T2/FLAIR hyperintense volume to the volume of contrast enhancement and necrosis was calculated.The volume of contrast enhancement, volume of central necrosis, combined volume of contrast enhancement and central necrosis, and the ratio of T2/FLAIR to contrast enhancement and necrosis were significantly different in MES compared with non-MES GBM (Mann-Whitney, P < .05). Receiver-operator characteristics indicated that these 4 metrics were all significant predictors of the MES phenotype. The volume ratio of T2 hyperintensity to contrast enhancement and central necrosis was significantly lower in MES vs non-MES GBM (P < .0001), was a significant predictor of the MES phenotype (area under the curve = 0.93, P < .001), and could be used to stratify short- and long-term overall survival (log-rank, P = .0064 using cutoff of 3.0). These trends were also present when excluding isocitrate dehydrogenase 1 mutant tumors and incorporating covariates such as age and KPS score.Results suggest that volume ratio may be a simple, cost-effective, and noninvasive biomarker for quickly identifying MES GBM.
CD8+ T Cell Effector Mechanisms in Resistance to Infection
Authors: John T. Harty, Amy R. Tvinnereim, Douglas W. White
Journal: Annual Review of Immunology (2000)

Based on T cell subset depletion studies and the analysis of gene knockout mice, it is evident that CD8 + T cells contribute to resistance against intracellular infections with certain viral, protozoan, and bacterial pathogens. Although they are known primarily for their capacity to kill infected cells, CD8 + T cells elaborate a variety of effector mechanisms with the potential to defend against infection. Microbes use multiple strategies to cause infection, and the nature of the pathogenhost interaction may determine which CD8 + T cell effector mechanisms are required for immunity. In this review, we summarize our current understanding of the effector functions used by CD8 + T cells in resistance to pathogens. Analyses of mice deficient in perforin and/or Fas demonstrate that cytolysis is critical for immunity against some, but not all, infections and also reveal the contribution of cytolysis to the pathogenesis of disease. The role of CD8 + T cell–derived cytokines in resistance to infection has been analyzed by systemic treatment with neutralizing antibodies and cytokine gene knockout mice. These studies are complicated by the fact that few, if any, cytokines are uniquely produced by CD8 + T cells. Thus, the requirement for CD8 + T cell– derived cytokines in resistance against most pathogens remains to be defined. Finally, recent studies of human CD8 + T cells reveal the potential for novel effector mechanisms in resistance to infection.