tbuckley/cabot-search huggingface dataset:
Overexpression of HAX-1 Protects Cardiac Myocytes From Apoptosis Through Caspase-9 Inhibition
Authors: Yuchi Han, Yee-Shiuan Chen, Zhilin Liu, Natalya Bodyak, Debra Rigor, Egbert Bisping, William T. Pu, Peter M. Kang
Journal: Circulation Research (2006)

Caspase-9 is a critical regulator of mitochondria-mediated apoptosis. We found that adult cardiac myocytes, but not nonmyocytes, have high caspase-9 expression, and exhibit relative resistance to caspase-9-induced cell death. Thus, we hypothesized that cardiac myocytes possess factors that resist apoptosis. Through a yeast two-hybrid screening of adult human heart cDNA library, we identified HS-1 associated protein-1 (HAX-1), a 35-kD BH-domain containing protein localized to the mitochondria as one of the molecules that interacts with caspase-9. Recombinant HAX-1 protein inhibited caspase-9 processing in a dose-dependent manner in a cell-free caspase activation assay. Overexpression of HAX-1 in adult cardiac myocytes conferred 30% protection from apoptosis as compared with the control. Suppression of HAX-1 expression using siRNA-HAX-1 resulted in significant cell death in adult cardiac myocytes, suggesting the importance of HAX-1 in cardiac myocyte resistance to apoptotic stimulation. On apoptotic stimulation, some caspase-9 translocated to the mitochondria and co-localized with HAX-1, confirming the spatial proximity of caspase-9 and HAX-1. In summary, HAX-1 is a newly identified anti-apoptotic factor and its mechanism of action is through caspase-9 inhibition.
Antibodies and Brain Disease: A Convergence of Immunology and Physiology
Authors: Betty Diamond, Bruce T Volpe
Journal: PLoS Medicine (2006)

Increasingly, patients with systemic lupus erythematosus (SLE) are recognized to have central nervous system (CNS) manifestations. Overt inflammation in the CNS is rare, but impairment of cognition or mood disturbance is common. Treatment of inflammation is directed at the underlying autoimmune disorder; treatment of other manifestations, including mood disorder, often focuses on symptom alleviation. Cognitive impairment in particular appears to be progressive and unrelated to disease activity, and, at the present time, untreatable. One interesting aspect of neuropsychiatric lupus is that symptoms may remit as well as progress.

With no known pathophysiology for the cognitive impairment or mood disturbance seen in SLE, and no ability to track the dynamic state of either of these symptom complexes, it has been difficult to develop a meaningful classification of neuropsychiatric SLE or a mechanistic understanding of these aspects of the disease process. There is possible mechanistic precedent for neuropsychiatric lupus in a number of disease syndromes in which anti-neuronal antibodies cause damage in the CNS. Often these antibodies arise as a consequence of microbial infection and cross-react with microbial antigens, as in post-streptococcal movement disorders [1], post-infectious polyradiculopathies [2], and tropical spastic paraparesis [3].
Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity
Authors: Arnab Ghosh, Yildirim Dogan, Maxim Moroz, Amanda M. Holland, Nury L. Yim, Uttam K. Rao, Lauren F. Young, Daniel Tannenbaum, Durva Masih, Enrico Velardi, Jennifer J. Tsai, Robert R. Jenq, Olaf Penack, Alan M. Hanash, Odette M. Smith, Kelly Piersanti, Cecilia Lezcano, George F. Murphy, Chen Liu, M. Lia Palomba, Martin G. Sauer, Michel Sadelain, Vladimir Ponomarev, Marcel R.M. van den Brink
Journal: Journal of Clinical Investigation (2013)

Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.
Advances in Antibody Design
Authors: Kathryn E. Tiller, Peter M. Tessier
Journal: Annual Review of Biomedical Engineering (2015)

The use of monoclonal antibodies as therapeutics requires optimizing several of their key attributes. These include binding affinity and specificity, folding stability, solubility, pharmacokinetics, effector functions, and compatibility with the attachment of additional antibody domains (bispecific antibodies) and cytotoxic drugs (antibody-drug conjugates). Addressing these and other challenges requires the use of systematic design methods that complement powerful immunization and in vitro screening methods. We review advances in designing the binding loops, scaffolds, domain interfaces, constant regions, post-translational and chemical modifications, and bispecific architectures of antibodies and fragments thereof to improve their bioactivity. We also highlight unmet challenges in antibody design that must be overcome to generate potent antibody therapeutics.
Prevalence of periarticular calcifications in pyrophosphate arthropathy and their relation to nodal osteoarthrosis.
Authors: J C Gerster, G Rappoport, J M Ginalski
Journal: Annals of the Rheumatic Diseases (1984)

X-rays of the shoulder, hand, and knee joints from 30 patients with pyrophosphate arthropathy (PA) and 30 age and sex matched control subjects were examined for periarticular, dense, homogeneous calcifications considered to be apatite deposits. They were found in 30% of the patients with PA compared with 3.3% of the controls. In addition in the PA group the incidence of Heberden's nodes was significantly increased in cases with periarticular calcifications, implying that mixed (calcium pyrophosphate dihydrate + apatite) crystal deposition disease could be related to nodal osteoarthrosis.
HLA-DRw6 as a risk factor for active cytomegalovirus but not for herpes simplex virus infection after renal allograft transplantation.
Authors: H W Roenhorst, A M Tegzess, J M Beelen, J M Middeldorp, T H The
Journal: BMJ (1985)

To study genetically determined susceptibility to cytomegalovirus and herpes simplex virus infections in patients given renal transplants a prospective study was performed of 68 consecutive patients receiving their first cadaveric kidney allograft. The recipients positive for HLA-DRw6 showed a significantly increased incidence of active cytomegalovirus infection as early as the 10th week after transplantation (p less than 0.05). No relation with other human leucocyte antigens was found, nor did a correlation exist between HLA typing and the incidence of herpes simplex virus infections. Furthermore, recipients positive for HLA-DRw6 with secondary cytomegalovirus infections excreted infectious virus more often (p less than 0.01) and showed more clinical symptoms (p less than 0.01) than a comparable group of recipients negative for HLA-DRw6. These observations may have practical implications for the treatment of patients who have had renal transplant operations.
Medullary but not cortical thymic epithelial cells present soluble antigens to helper T cells.
Authors: T Mizuochi, M Kasai, T Kokuho, T Kakiuchi, K Hirokawa
Journal: The Journal of Experimental Medicine (1992)

Thymic epithelial cell lines (TECs) were established from newborn C57BL/6 mice. They were classified into two types (medullary and cortical TECs) by using the monoclonal antibody (Th-3) that recognizes the meshwork structure of thymic cortical epithelial cells. Antigen-presenting activity of each TEC was determined by using ovalbumin-specific, I-Ab-restricted helper T cell lines. It was demonstrated that the medullary but not the cortical TECs functioned as antigen-presenting cells. This is the first evidence for the functional difference between the cortical and the medullary TEC.
Frequency Analysis of the Electrocardiogram
Authors: ALLEN M. SCHER, ALLAN C. YOUNG
Journal: Circulation Research (1960)

The frequency analysis of the electrocardiogram reveals that contributions by frequencies of 100 cycles, or higher, per second are less than 10 per cent of the amplitude of the fundamental of the QRS comples, and it thus appears that transistor-driven amplifier-pen recorders presently available are adequate to record all the information contained in the electrocardiogram, if the standard paper speed is doubled, or quadrupled.
High-throughput molecular analysis in lung cancer: insights into biology and potential clinical applications
Authors: S. Ocak, M. L. Sos, R. K. Thomas, P. P. Massion
Journal: European Respiratory Journal (2009)

During the last decade, high-throughput technologies including genomic, epigenomic, transcriptomic and proteomic have been applied to further our understanding of the molecular pathogenesis of this heterogeneous disease, and to develop strategies that aim to improve the management of patients with lung cancer. Ultimately, these approaches should lead to sensitive, specific and noninvasive methods for early diagnosis, and facilitate the prediction of response to therapy and outcome, as well as the identification of potential novel therapeutic targets. Genomic studies were the first to move this field forward by providing novel insights into the molecular biology of lung cancer and by generating candidate biomarkers of disease progression. Lung carcinogenesis is driven by genetic and epigenetic alterations that cause aberrant gene function; however, the challenge remains to pinpoint the key regulatory control mechanisms and to distinguish driver from passenger alterations that may have a small but additive effect on cancer development. Epigenetic regulation by DNA methylation and histone modifications modulate chromatin structure and, in turn, either activate or silence gene expression. Proteomic approaches critically complement these molecular studies, as the phenotype of a cancer cell is determined by proteins and cannot be predicted by genomics or transcriptomics alone. The present article focuses on the technological platforms available and some proposed clinical applications. We illustrate herein how the "-omics" have revolutionised our approach to lung cancer biology and hold promise for personalised management of lung cancer.
Are Markers of Inflammation More Strongly Associated with Risk for Fatal Than for Nonfatal Vascular Events?
Authors: Naveed Sattar, Heather M. Murray, Paul Welsh, Gerard J. Blauw, Brendan M. Buckley, Stuart Cobbe, Anton J. M. de Craen, Gordon D. Lowe, J. Wouter Jukema, Peter W. Macfarlane, Michael B. Murphy, David J. Stott, Rudi G. J. Westendorp, James Shepherd, Ian Ford, Chris J. Packard
Journal: PLoS Medicine (2009)

In a secondary analysis of a randomized trial comparing pravastatin versus placebo for the prevention of coronary and cerebral events in an elderly at-risk population, Naveed Sattar and colleagues find that inflammatory markers may be more strongly associated with risk of fatal vascular events than nonfatal vascular events.
An overview of asthma and airway hyper-responsiveness in Olympic athletes
Authors: Kenneth D Fitch
Journal: British Journal of Sports Medicine (2012)

Data from the past five Olympic Games obtained from athletes seeking to inhale β2 adrenoceptor agonists (IBA) have identified those athletes with documented asthma and airway hyper-responsiveness (AHR). With a prevalence of about 8%, asthma/AHR is the commonest chronic medical condition experienced by Olympic athletes. In Summer and Winter athletes, there is a marked preponderance of asthma/AHR in endurance-trained athletes. The relatively late onset of asthma/AHR in many older athletes is suggestive that years of endurance training may be a contributory cause. Inspiring polluted or cold air is considered a significant aetiological factor in some but not all sports. During the last five Olympic Games, there has been improved management of athletes with asthma/AHR with a much higher proportion of athletes combining inhaled corticosteroids (ICS) with IBA and few using long-acting IBA as monotherapy. Athletes with asthma/AHR have consistently outperformed their peers, which research suggests is not due to their treatment enhancing sports performance. Research is necessary to determine how many athletes will continue to experience asthma/AHR in the years after they cease intensive endurance training.
Suppression of Glucosylceramide Synthase Restores p53-Dependent Apoptosis in Mutant p53 Cancer Cells
Authors: Yong-Yu Liu, Gauri A. Patwardhan, Kaustubh Bhinge, Vineet Gupta, Xin Gu, S. Michal Jazwinski
Journal: Cancer Research (2011)

Tumor suppressor p53 plays an essential role in protecting cells from malignant transformation by inducing cell-cycle arrest and apoptosis. Mutant p53 that is detected in more than 50% of cases of cancers loses its role in suppression of tumors but gains in oncogenic function. Strategies to convert mutant p53 into wild-type p53 have been suggested for cancer prevention and treatment, but they face a variety of challenges. Here, we report an alternative approach that involves suppression of glucosylceramide synthase (GCS), an enzyme that glycosylates ceramide and blunts its proapoptotic activity in cancer cells. Human ovarian cancer cells expressing mutant p53 displayed resistance to apoptosis induced by DNA damage. We found that GCS silencing sensitized these mutant p53 cells to doxorubicin but did not affect the sensitivity of cells with wild-type p53. GCS silencing increased the levels of phosphorylated p53 and p53-responsive genes, including p21(Waf1/Cip1), Bax, and Puma, consistent with a redirection of the mutant p53 cells to apoptosis. Reactivated p53-dependent apoptosis was similarly verified in p53-mutant tumors where GCS was silenced. Inhibition of ceramide synthase with fumonisin B1 prevented p53 reactivation induced by GCS silencing, whereas addition of exogenous C6-ceramide reactivated p53 function in p53-mutant cells. Our findings indicate that restoring active ceramide to cells can resuscitate wild-type p53 function in p53-mutant cells, offering preclinical support for a novel type of mechanism-based therapy in the many human cancers harboring p53 mutations.
Decreases in Diameters of Treated Abdominal Aortic Aneurysms and Reduction in Rupture Rate
Authors: Anoushiravan Amini Hadjibashi, James Mirocha, David V. Cossman, Bruce L. Gewertz
Journal: JAMA Surgery (2012)

To determine whether the diameters of treated abdominal aortic aneurysms (AAAs) have changed during the last 10 years.A retrospective record review was completed on all patients undergoing any AAA repair from January 1, 2000, through December 31, 2009, at a single high-volume institution. All cases of repaired AAAs that had computed tomographic scans within 3 months of surgery were included. The mean and median maximal diameters of AAAs were noted. Correlation and regression analyses were used.The mean and median maximal diameters of AAAs.Of 360 patients with treated AAAs, 339 met the inclusion criteria. The mean (SD) diameter of repaired AAAs decreased from 6.49 (1.46) cm (median, 6.40 cm) in 2000 to 5.83 (1.23) cm (median, 5.60 cm) in 2009. Correlation analysis confirmed a decrease in diameter across years (Pearson R = -0.141; P = .01). A fitted regression line also showed a decreasing trend (slope = -0.059 cm per year; P = .01).The diameters of repaired AAAs at our hospital have decreased progressively during the last decade. This observation is consistent with a reduction in the expansion rates of AAAs and may account for the progressive decreases in the aneurysm rupture rate in the United States.
New Equations to Estimate GFR in Children with CKD
Authors: George J. Schwartz, Alvaro Mun[Combining Tilde]oz, Michael F. Schneider, Robert H. Mak, Frederick Kaskel, Bradley A. Warady, Susan L. Furth
Journal: Journal of the American Society of Nephrology (2009)

The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.
Value of Prospective Tissue Typing in Kidney Transplantation Between HL-A Identical Siblings
Authors: R. Patel, S. Myrberg
Journal: BMJ (1970)

The predictability of leucocyte typing in kidney transplantation was assessed by an analysis of 37 kidney transplants from sibling donors. Recipients who were identical for the HL-A antigens with their donors gave highly predictable results. In comparison with those siblings who were incompatible or compatible but not identical their grafts functioned earlier, they required less immunosuppression, and had never had any rejections. They also appeared to have less postoperative morbidity. These results indicate that less immunosuppression than is current in many transplant centres could well be used with benefit in HL-A identical sibling transplants. This could reduce the risk of infection and possibly minimize the adverse effects of steroids on wound healing in these patients.
Oral intake of phosphorus can determine the serum concentration of 1,25-dihydroxyvitamin D by determining its production rate in humans.
Authors: A A Portale, B P Halloran, M M Murphy, R C Morris
Journal: Journal of Clinical Investigation (1986)

Changes in the oral intake of phosphorus could induce the reported changes in the serum concentration of 1,25-dihydroxyvitamin D (1,25-(OH)2D) by inducing changes in its production rate (PR) or metabolic clearance rate (MCR), or both. To investigate these possibilities, we employed the constant infusion equilibrium technique to measure the PR and MCR of 1,25-(OH)2D in six healthy men in whom the oral intake of phosphorus was initially maintained at 1,500 mg/70 kg body weight per d for 9 d, then restricted to 500 mg/d (coupled with oral administration of aluminum hydroxide) for 10 d, and then supplemented to 3,000 mg/d for 10 d. With phosphorus restriction, the serum concentration of 1,25-(OH)2D increased by 80% from a mean of 38 +/- 3 to 68 +/- 6 pg/ml, P less than 0.001; the PR increased from 1.8 +/- 0.2 to 3.8 +/- 0.6 micrograms/d, P less than 0.005; the MCR did not change significantly. The fasting serum concentration of phosphorus decreased from 3.5 +/- 0.2 to 2.6 +/- 0.2 mg/dl, P less than 0.01. With phosphorus supplementation, the serum concentration of 1,25-(OH)2D decreased abruptly, reaching a nadir within 2 to 4 d; after 10 d of supplementation, the mean concentration of 27 +/- 4 pg/ml was lower by 29%, P less than 0.01, than the value measured when phosphorus intake was normal. The PR decreased to 1.3 +/- 0.2 micrograms/d, P less than 0.05; the MCR did not change significantly. The fasting serum concentration of phosphorus increased significantly, but only initially. These data demonstrate that in healthy men, reductions and increases in the oral intake of phosphorus can induce rapidly occurring, large, inverse, and persisting changes in the serum concentration of 1,25-(OH)2D. Changes in the PR of 1,25-(OH)2D account entirely for the phosphorus-induced changes in serum concentration of this hormone.
Prevalence and prognosis of COPD in critically ill patients between 1998 and 2008
Authors: Georg-Christian Funk, Peter Bauer, Otto Chris Burghuber, Andreas Fazekas, Sylvia Hartl, Helene Hochrieser, Rene Schmutz, Philipp Metnitz
Journal: European Respiratory Journal (2012)

The epidemiology of chronic obstructive pulmonary disease (COPD) in critically ill patients is largely unknown. The aims of the study were: 1) to determine whether COPD, either as the cause of intensive care unit (ICU) admission or as a comorbid condition, is an independent risk factor for increased morbidity and mortality; and 2) to investigate time trends in proportion and outcome of acute respiratory failure in patients with COPD admitted to ICUs. Prospectively recorded data from 194 453 adults consecutively admitted to 87 Austrian ICUs over a period of 11 years (1998-2008) were retrospectively analysed. COPD was present in 8.6% of all patients. The risk-adjusted mortality of patients with COPD was higher than in patients without COPD. The presence of COPD was an independent risk factor for increased mortality and was associated with prolonged mechanical ventilation and prolonged weaning. During the course of the 11 years, the proportion of acute respiratory failure due to COPD increased by about two-thirds, and the use of noninvasive ventilation within the COPD cohort more than doubled. Simultaneously, the risk-adjusted mortality of patients with COPD improved. In critically ill patients, the presence of COPD is increasing and is an independent risk factor for mortality and morbidity.