tbuckley/cabot-search huggingface dataset:
Adipocyte LDL receptor–related protein–1 expression modulates postprandial lipid transport and glucose homeostasis in mice
Authors: Susanna M. Hofmann, Li Zhou, Diego Perez-Tilve, Todd Greer, Erin Grant, Lauren Wancata, Andrew Thomas, Paul T. Pfluger, Joshua E. Basford, Dean Gilham, Joachim Herz, Matthias H. Tschöp, David Y. Hui
Journal: Journal of Clinical Investigation (2007)

Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure.
The Nottingham Eczema Severity Score: preliminary refinement of the Rajka and Langeland grading
Authors: R.M. Emerson, C.R. Charman, H.C. Williams
Journal: British Journal of Dermatology (2000)

A method for assessing disease severity of atopic dermatitis (AD) in children has been developed for population-based research. Based on an index first described by Rajka and Langeland in 1989, disease severity is determined by evaluating the three elements of clinical course, disease intensity and extent of examined AD. This paper describes development of the index for use in epidemiological studies based on a community-based study of 290 pre-school children (aged 1-5 years). Construct validity of the index was evaluated with respect to clinical severity assessment according to a dermatologist, parental severity assessment, use of topical corticosteroids and impairment of quality of life. The severity distribution of AD in this community-based sample of children was: mild 82% (n = 237), moderate 12% (n = 36) and severe 6% (n = 17) according to this new index. In this sample 24% of children had suffered from AD of more than 9 months duration in the preceding 12 months, 4.5% had experienced significant sleep loss (6 or more nights of average sleep loss per week over 12 months) and 11% had experienced widespread extent of involvement (more than 10 body sites involved). Construct validity of the index was demonstrated for clinical and patient-derived severity assessment. This included a comparison between the new index and a global severity assessment by a dermatologist in which exact agreement was achieved in 88% of the cases. A small subgroup of children suffering from persistent localized forms of AD (discoid pattern, hand/ foot dermatitis, perioral dermatitis), who reported considerable morbidity, was identified using quality of life measures of severity; they would otherwise have been misclassified by the dermatologist or new index. Preliminary use of the Nottingham Eczema Severity Score would support further development as a research tool for a simple assessment of disease severity that could be used in epidemiological studies. Further validation is required with respect to use in older children, administration by researchers/health professionals and development as a wholly questionnaire-based assessment.
Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex.
Authors: M Thome, P Duplay, M Guttinger, O Acuto
Journal: The Journal of Experimental Medicine (1995)

During antigen recognition by T cells, CD4 and the T-cell receptor (TCR)/CD3/zeta complex are thought to interact with the same major histocompatibility complex II molecule in a stable ternary complex. Evidence has suggested that the association of CD4 with TCR/CD3/zeta requires the interaction of the protein tyrosine kinase p56lck with CD4. We have taken a biochemical approach to understand the mechanism by which p56lck and, in particular, its src homology (SH) 2 domain contributes to the association of CD4 with TCR/CD3/zeta during activation. We have previously shown that the p56lck SH2 domain binds directly to tyrosine-phosphorylated ZAP-70. Here we formally demonstrate the in vivo association of p56lck with the homologous protein tyrosine kinases Syk and ZAP-70 after CD3 stimulation of Jurkat cells. A tyrosine-phosphorylated peptide containing the sequence predicted to be optimal for binding to the SH2 domain of src family kinases specifically competes for this association, indicating that tyrosine-phosphorylated ZAP-70 and Syk bind to p56lck by an SH2-mediated interaction. We also show that the same peptide is able to compete for the activation-dependent TCR/CD4 association in Jurkat cells. Moreover, ZAP-70 and CD4 cocap only after CD3 stimulation in human T lymphoblasts. We propose that the interaction of the p56lck SH2 domain with zeta-associated tyrosine-phosphorylated ZAP-70 and/or Syk enables CD4 to associate with antigen-stimulated TCR/CD3/zeta complexes.
The Natural History of Residual Renal Function in Transplant Donors
Authors: Thomas F. Mueller, Valerie A. Luyckx
Journal: Journal of the American Society of Nephrology (2012)

After uninephrectomy, GFR in the remaining kidney increases to 60%-70% of the predonation value, largely because of a substantial increase in renal blood flow. Donor kidney function is then generally maintained over many years. Hypertension and proteinuria are common among living donors but do not appear to negatively affect long-term renal function. Loss of reserve capacity regarding renal function in some subgroups after donation, particularly in obese and older donors, raises questions about limitations of the renal adaptive response and suggests caution in generalization of current outcome data to more marginal donors not well represented in older studies.
Effect of Multikinase Inhibitors on Caspase-Independent Cell Death and DNA Damage in HER2-Overexpressing Breast Cancer Cells
Authors: Samuel Seoane, Juan Carlos Montero, Alberto Ocaña, Atanasio Pandiella
Journal: JNCI Journal of the National Cancer Institute (2010)

The receptor tyrosine kinase, HER2, is overexpressed in approximately 25% of patients with breast cancer and is implicated in the aggressiveness of cancer. Targeting of HER2 signaling with trastuzumab, a monoclonal antibody that inhibits HER2 activity, has demonstrated clinical benefits.We investigated whether the antitumor activity of trastuzumab can be potentiated by dasatinib, a small-molecule tyrosine kinase inhibitor, on breast cancer cell lines that overexpress HER2 (BT474 and SKBR3) or have normal HER2 expression (MCF7 and T47D). Functional, biochemical, and gene expression microarray studies were performed to test the effect of trastuzumab, dasatinib, or a combination of trastuzumab and dasatinib on cell proliferation; HER activation; cell cycle; DNA damage; and apoptosis. The effect of drugs on mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells was assessed, and tumors were evaluated for an effect on volume, HER signaling, and DNA damage. All statistical tests were two-sided.Trastuzumab and dasatinib combination showed a synergistic effect on the proliferation of HER2-overexpressing breast cancer cells (combination index = 0.44, 95% confidence interval = 0.30 to 0.58). The drug combination also induced a stronger inhibitory effect on HER2 activation than the individual drugs, decreased the level of proteins involved in DNA damage response, induced DNA double-strand breaks, cell cycle arrest, and caspase-independent apoptosis. Mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells showed statistically significantly reduced tumor volume on day 28 when treated with the drug combination (control vs trastuzumab and dasatinib combination; mean volume = 2.6 vs 0.5 cm(3), difference = 2.1 cm(3), 95% confidence interval = 0.76 to 3.51 cm(3), P = .01) and total regression of tumors by day 36 with no later relapse.Results showed that HER2 and dasatinib-sensitive tyrosine kinases act in a synergistic manner to safeguard the breast cancer cells from DNA damage. The therapeutic targeting of multikinase inhibition opens new avenues for the treatment of HER2-positive breast cancer patients.
A prospective randomized phase II trial of GM-CSF priming to prevent topotecan-induced neutropenia in chemotherapy-naive patients with malignant melanoma or renal cell carcinoma
Authors: John E. Janik, Langdon L. Miller, Edward L. Korn, Diane Stevens, Brendan D. Curti, John W. Smith, Mario Sznol, Kevin C. Conlon, William Sharfman, Walter J. Urba, Barry L. Gause, Dan L. Longo
Journal: Blood (2001)
SPONTANEOUS REDUCTION OF INTUSSUSCEPTION
Authors: T. B. Henderson
Journal: BMJ (1912)

alive to the immense difficulty that there is in many cases -so great as to make a sure diagnosis in some cases im- possible, especially in stout people and in pregnant women.In the majority of instances, however, it is not because a diagnosis has not been made, but rather because, having been made, it has not been acted upon, that so many cases come to the surgeon with complications. SPONTANEOUS REDUCTION OF INTUS-SUSCEPTION.
Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation
Authors: Aude Magerus-Chatinet, Bénédicte Neven, Marie-Claude Stolzenberg, Cécile Daussy, Peter D. Arkwright, Nina Lanzarotti, Catherine Schaffner, Sophie Cluet-Dennetiere, Filomeen Haerynck, Gérard Michel, Christine Bole-Feysot, Mohammed Zarhrate, Isabelle Radford-Weiss, Serge P. Romana, Capucine Picard, Alain Fischer, Frédéric Rieux-Laucat
Journal: Journal of Clinical Investigation (2010)

Autoimmune diseases develop in approximately 5% of humans. They can arise when self-tolerance checkpoints of the immune system are bypassed as a consequence of inherited mutations of key genes involved in lymphocyte activation, survival, or death. For example, autoimmune lymphoproliferative syndrome (ALPS) results from defects in self-tolerance checkpoints as a consequence of mutations in the death receptor–encoding gene TNF receptor superfamily, member 6 (TNFRSF6; also known as FAS). However, some mutation carriers remain asymptomatic throughout life. We have now demonstrated in 7 ALPS patients that the disease develops as a consequence of an inherited TNFRSF6 heterozygous mutation combined with a somatic genetic event in the second TNFRSF6 allele. Analysis of the patients' CD4–CD8– (double negative) T cells — accumulation of which is a hallmark of ALPS — revealed that in these cells, 3 patients had somatic mutations in their second TNFRSF6 allele, while 4 patients had loss of heterozygosity by telomeric uniparental disomy of chromosome 10. This observation provides the molecular bases of a nonmalignant autoimmune disease development in humans and may shed light on the mechanism underlying the occurrence of other autoimmune diseases.
Hemodynamic and Cellular Response Feedback in Calcific Aortic Valve Disease
Authors: Sarah T. Gould, Suthan Srigunapalan, Craig A. Simmons, Kristi S. Anseth
Journal: Circulation Research (2013)

This review highlights aspects of calcific aortic valve disease that encompass the entire range of aortic valve disease progression from initial cellular changes to aortic valve sclerosis and stenosis, which can be initiated by changes in blood flow (hemodynamics) and pressure across the aortic valve. Appropriate hemodynamics is important for normal valve function and maintenance, but pathological blood velocities and pressure can have profound consequences at the macroscopic to microscopic scales. At the macroscopic scale, hemodynamic forces impart shear stresses on the surface of the valve leaflets and cause deformation of the leaflet tissue. As discussed in this review, these macroscale forces are transduced to the microscale, where they influence the functions of the valvular endothelial cells that line the leaflet surface and the valvular interstitial cells that populate the valve extracellular matrix. For example, pathological changes in blood flow–induced shear stress can cause dysfunction, impairing their homeostatic functions, and pathological stretching of valve tissue caused by elevated transvalvular pressure can activate valvular interstitial cells and latent paracrine signaling cytokines (eg, transforming growth factor-β1) to promote maladaptive tissue remodeling. Collectively, these coordinated and complex interactions adversely impact bulk valve tissue properties, feeding back to further deteriorate valve function and propagate valve cell pathological responses. Here, we review the role of hemodynamic forces in calcific aortic valve disease initiation and progression, with focus on cellular responses and how they feed back to exacerbate aortic valve dysfunction.
N-acetylcysteine increases manganese superoxide dismutase activity in septic rat diaphragms
Authors: E. Barreiro, D. Sánchez, J. B. Gáldiz, S. N. A. Hussain, J. Gea
Journal: European Respiratory Journal (2005)

The antioxidant N-acetylcysteine (NAC) prevented sepsis-induced diaphragmatic dysfunction. As an indirect antioxidant NAC was shown to induce superoxide dismutase (SOD) activity in immune cells from endotoxaemic mice. The aim of this study was to assess whether NAC acts as an indirect antioxidant by inducing manganese (Mn)-SOD activity in the diaphragms of endotoxaemic rats, while preventing muscle dysfunction. A controlled study was conducted, in which protein carbonylation, Mn-SOD, catalase, and 3-nitrotyrosine immunoreactivity were detected using immunoblotting and immunohistochemistry in rat diaphragms. Six groups were studied for 24 h after a saline (control) or lipopolysaccharide (LPS; 20 mg.kg-1) i.p. injection in the absence and presence of NAC pre-treatment (either 1.5 or 3 mmol.kg(-1).24 h-1 for 7 days, oral administration). Diaphragm mitochondrial Mn-SOD activity and respiratory muscle function were also determined. Within 24 h, LPS induced maximal inspiratory pressure reduction, increasing diaphragmatic protein carbonylation and nitration. Pre-treatment with 3 mmol.kg-1 NAC clearly increased muscle Mn-SOD protein content and activity in both LPS- and saline-injected animals, while reducing protein carbonylation and nitration, and partially preventing the LPS-induced respiratory muscle dysfunction. Data produced from this study indicate that high doses of N-acetylcysteine induces manganese superoxide dismutase, as well as preserves its activity, possibly by preventing nitration of critical tyrosine residues of the enzyme.
Living and dying with severe chronic obstructive pulmonary disease: multi-perspective longitudinal qualitative study
Authors: H. Pinnock, M. Kendall, S. A. Murray, A. Worth, P. Levack, M. Porter, W. MacNee, A. Sheikh
Journal: BMJ (2011)

<b>Objectives</b> To understand the perspectives of people with severe chronic obstructive pulmonary disease (COPD) as their illness progresses, and of their informal and professional carers, to inform provision of care for people living and dying with COPD. <b>Design</b> Up to four serial qualitative interviews were conducted with each patient and nominated carer over 18 months. Interviews were transcribed and analysed both thematically and as narratives. <b>Participants</b> 21 patients, and 13 informal carers (a family member, friend, or neighbour) and 18 professional carers (a key health or social care professional) nominated by the patients. <b>Setting</b> Primary and secondary care in Lothian, Tayside, and Forth Valley, Scotland, during 2007-9. <b>Results</b> Eleven patients died during the study period. Our final dataset comprised 92 interviews (23 conducted with patient and informal carer together). Severe symptoms that caused major disruption to normal life were described, often in terms implying acceptance of the situation as a "way of life" rather than an "illness." Patients and their informal carers adapted to and accepted the debilitating symptoms of a lifelong condition. Professional carers' familiarity with the patients' condition, typically over many years, and prognostic uncertainty contributed to the difficulty of recognising and actively managing end stage disease. Overall, patients told a "chaos narrative" of their illness that was indistinguishable from their life story, with no clear beginning and an unanticipated end described in terms comparable with attitudes to death in a normal elderly population. <b>Conclusions</b> Our findings challenge current assumptions underpinning provision of end of life care for people with COPD. The policy focus on identifying a time point for transition to palliative care has little resonance for people with COPD or their clinicians and is counter productive if it distracts from early phased introduction of supportive care. Careful assessment of possible supportive and palliative care needs should be triggered at key disease milestones along a lifetime journey with COPD, in particular after hospital admission for an exacerbation.
Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response
Authors: Marcus Odendahl, Henrik Mei, Bimba F. Hoyer, Annett M. Jacobi, Arne Hansen, Gwendolin Muehlinghaus, Claudia Berek, Falk Hiepe, Rudi Manz, Andreas Radbruch, Thomas Dörner
Journal: Blood (2004)
An epidemiological study of pulmonary arterial hypertension
Authors: A. J. Peacock, N. F. Murphy, J. J. V. McMurray, L. Caballero, S. Stewart
Journal: European Respiratory Journal (2007)

All hospitalisations for pulmonary arterial hypertension (PAH) in the Scottish population were examined to determine the epidemiological features of PAH. These data were compared with expert data from the Scottish Pulmonary Vascular Unit (SPVU). Using the linked Scottish Morbidity Record scheme, data from all adults aged 16–65 yrs admitted with PAH (idiopathic PAH, pulmonary hypertension associated with congenital heart abnormalities and pulmonary hypertension associated with connective tissue disorders) during the period 1986–2001 were identified. These data were compared with the most recent data in the SPVU database (2005). Overall, 374 Scottish males and females aged 16–65 yrs were hospitalised with incident PAH during 1986–2001. The annual incidence of PAH was 7.1 cases per million population. On December 31, 2002, there were 165 surviving cases, giving a prevalence of PAH of 52 cases per million population. Data from the SPVU were available for 1997–2006. In 2005, the last year with a complete data set, the incidence of PAH was 7.6 cases per million population and the corresponding prevalence was 26 cases per million population. Hospitalisation data from the Scottish Morbidity Record scheme gave higher prevalences of pulmonary arterial hypertension than data from the expert centres (Scotland and France). The hospitalisation data may overestimate the true frequency of pulmonary arterial hypertension in the population, but it is also possible that the expert centres underestimate the true frequency.
BEX2 has a functional interplay with c-Jun/JNK and p65/RelA in breast cancer
Authors: Ali Naderi, Ji Liu, Luke Hughes-Davies
Journal: Molecular Cancer (2010)

We have previously demonstrated that BEX2 is differentially expressed in breast tumors and has a significant role in promoting cell survival and growth in breast cancer cells. BEX2 expression protects breast cancer cells against mitochondrial apoptosis and G1 cell cycle arrest. In this study we investigated the transcriptional regulation of BEX2 and feedback mechanisms mediating the cellular function of this gene in breast cancer.We found a marked induction of BEX2 promoter by c-Jun and p65/RelA using luciferase reporter assays in MCF-7 cells. Furthermore, we confirmed the binding of c-Jun and p65/RelA to the BEX2 promoter using a chromatin immunoprecipitation assay. Importantly, transfections of c-Jun or p65/RelA in MCF-7 cells markedly increased the expression of BEX2 protein. Overall, these results demonstrate that BEX2 is a target gene for c-Jun and p65/RelA in breast cancer. These findings were further supported by the presence of a strong correlation between BEX2 and c-Jun expression levels in primary breast tumors. Next we demonstrated that BEX2 has a feedback mechanism with c-Jun and p65/RelA in breast cancer. In this process BEX2 expression is required for the normal phosphorylation of p65 and IkappaB alpha, and the activation of p65. Moreover, it is necessary for the phosphorylation of c-Jun and JNK kinase activity in breast cancer cells. Furthermore, using c-Jun stable lines we showed that BEX2 expression is required for c-Jun mediated induction of cyclin D1 and cell proliferation. Importantly, BEX2 down-regulation resulted in a significant increase in PP2A activity in c-Jun stable lines providing a possible underlying mechanism for the regulatory effects of BEX2 on c-Jun and JNK.This study shows that BEX2 has a functional interplay with c-Jun and p65/RelA in breast cancer. In this process BEX2 is a target gene for c-Jun and p65/RelA and in turn regulates the phosphorylation/activity of these proteins. These suggest that BEX2 is involved in a novel feedback mechanism with significant implications for the biology of breast cancer.
Quantitative sports and functional classification (QSFC) for disabled people with spasticity
Authors: M A Khalili
Journal: British Journal of Sports Medicine (2004)

Although sports classification for cerebral palsy has been in use for several years, it is complicated both for training and for scoring. People with cerebral palsy are difficult to fit into classification systems that are appropriate for other disability groups. The aim of this report is to describe the development of a framework for a simple quantitative classification of cerebral palsy. It was designed to be easily understood by all who are investigating, treating, training, coaching, and working with spastic disabled people. The scoring system is accurate and quick, so long as the definitions of items listed are adhered to.