tbuckley/cabot-search huggingface dataset:
Decline in the growth potential of spleen-colonizing bone marrow stem cells of long-lived aging mice.
Authors: J W Albright, T Makinodan
Journal: The Journal of Experimental Medicine (1976)

The growth capacity of femoral bone marrow stem cells from young and old long-lived mice was assessed in the spleen of X-irradiated young and old syngeneic recpients by determining: (a) the number of stem cells colonizing the spleen, (b) the rate of incorporation of 125I-labeled iododeoxyuridine by proliferating colony cells, and (c) the number of cells present in the largest colonies at the end of the growth phase.We found that the growth capacity of stem cells declined with age. We further found that the spleen-seeking and spleen colony growth capacities of old stem cells remained characteristically old even after they were allowed to self-replicate in the bone marrow of young recipients for an extended period of time. On the other hand, the spleen colony growth capacity of young stem cells could be reduced by allowing them to self-replicate in old recipients. These results suggest that the growth capacity of old stem cells is an intrinsic characteristic which cannot be readily altered, but that of young stem cells can be aged in an accelerated manner by allowing them to self-replicate in old recipients. An additional reduction was noted in the frequency of both young and old stem cells colonizing the spleen of old recipients and in the cell density of the largest colonies produced. These results indicate that factors extrinsic to the stem cells are also responsible for the decline with age in their spleen colony growth capacity.Thus, the growth capacity of old stem cells in old recipients could be as low as 10% that of young stem cells in young recipients.
Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets
Authors: Jonathan D. Brown, Jorge Plutzky
Journal: Circulation (2007)

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the transcriptional regulation of key metabolic pathways such as lipid metabolism, adipogenesis, and insulin sensitivity. More recent work implicates all 3 PPAR isotypes (alpha, gamma, and delta, also known as beta or beta/delta) in inflammatory and atherosclerotic pathways. Because these nuclear receptors are activated by extracellular signals and control multiple gene targets, PPARs can be seen as nodes that control multiple inputs and outputs involved in energy balance, providing insight into how metabolism and the vasculature may be integrated. The ongoing clinical use of fibrates, which activate PPARalpha, and thiazolidinediones, which activate PPARgamma, establishes these receptors as viable drug targets, whereas considerable in vitro animal model and human surrogate marker studies suggest that PPAR activation may limit inflammation and atherosclerosis. Together, these various observations have stimulated intense interest in PPARs as therapeutic targets and led to large-scale cardiovascular end-point trials with PPAR agonists. The first of these studies has generated mixed results that require careful review, especially in anticipation of additional clinical trial data and ongoing attempts to develop novel PPAR modulators. Such analysis of the existing PPAR data, the appropriate use of currently approved PPAR agonists, and continued progress in PPAR therapeutics will be predicated on a better understanding of PPAR biology.
Pulse Pressure and Cardiovascular Disease–Related Mortality
Authors: Michael Domanski, Gary Mitchell, Marc Pfeffer, James D. Neaton, James Norman, Kenneth Svendsen, Richard Grimm, Jerome Cohen, Jeremiah Stamler, None for the MRFIT Research Group
Journal: JAMA (2002)

The sixth Joint National Committee (JNC-VI) classification system of blood pressure emphasizes both systolic blood pressure (SBP) and diastolic blood pressure (DBP) for cardiovascular disease risk assessment. Pulse pressure may also be a valuable risk assessment tool.To compare relationships of SBP, DBP, and pulse pressure, separately and jointly, with cardiovascular disease-related mortality in men.Data from the Multiple Risk Factor Intervention Trial (MRFIT), which screened men aged 35 to 57 years from 1973 through 1975 at 22 US centers, was used to assess cardiovascular disease-related mortality through 1996.A total of 342 815 men without diabetes or a history of myocardial infarction were divided into 2 groups based on their age at MRFIT screening (35- to 44-year-olds and 45- to 57-year olds). Participant blood pressure levels were classified into a JNC-VI blood pressure category based on SBP and DBP (optimal, normal but not optimal, high normal, stage 1 hypertension, stage 2-3 hypertension), and pulse pressure was calculated.Cardiovascular disease-related mortality.There were 25 721 cardiovascular disease-related deaths. Levels of SBP and DBP were more strongly related to cardiovascular disease than pulse pressure. Relationships of SBP, DBP, and pulse pressure to cardiovascular disease-related mortality varied within JNC-VI category. Concordant elevations of SBP and DBP were associated with a greater risk of cardiovascular disease-related mortality for both age groups of men. Among men aged 45 to 57 years, higher SBP and lower DBP (discordant elevations) also yielded a greater risk of cardiovascular disease-related mortality.In both age groups, cardiovascular disease risk assessment was improved by considering both SBP and DBP, not just SBP, DBP, or pulse pressure separately.
Risk factors of early redialysis after weaning from postoperative acute renal replacement therapy
Authors: Vin-Cent Wu, Wen-Je Ko, Hong-Wei Chang, Yung-Wei Chen, Yu-Feng Lin, Chih-Chung Shiao, Yung-Ming Chen, Yih-Sharng Chen, Pi-Ru Tsai, Fu-Chang Hu, Jann-Yuan Wang, Yen-Hung Lin, Kwan-Dun Wu
Journal: Intensive Care Medicine (2007)
HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group
Authors: S. Camilleri-Broët, A.C. Hardy-Bessard, A. Le Tourneau, D. Paraiso, O. Levrel, B. Leduc, S. Bain, H. Orfeuvre, J. Audouin, E. Pujade-Lauraine
Journal: Annals of Oncology (2003)

BackgroundDespite numerous studies, no biological marker has been identified that accurately predicts prognosis of advanced ovarian cancer. Tumors from a homogeneous population of 117 patients with a stage III/IV ovarian cancer, enrolled in a multicenter prospective GINECO clinical trial were analyzed retrospectively.Patients and methodsAll patients received the same platinum-based combination therapy and were followed-up for a median of 68 months. Tumor expression of Ki67, BCL-2, BAX, P53 or c-erbB-2 proteins was evaluated immunohistochemically on paraffin-embedded tissues and their prognostic impact analyzed.ResultsThe median rate of Ki67-positive nuclear area was 30%. BCL-2, BAX and P53 proteins were expressed in 52, 54 and 71% of the tumors, respectively, while HER-2 protein was overexpressed in 16%. Only HER-2 overexpression was significantly associated with shorter progression-free survival and overall survival. According to our multivariate analysis, the HER-2 prognostic impact was independent of classical clinical prognostic factors.ConclusionHER-2 appeared to influence the outcome of advanced ovarian cancer patients included in a clinical trial with prolonged follow-up, thereby suggesting that HER-2 is a potential target for treatment of this cancer.
Heart Failure in Rats Causes Changes in Skeletal Muscle Morphology and Gene Expression That Are Not Explained by Reduced Activity
Authors: Americo Simonini, Carlin S. Long, Gary A. Dudley, Ping Yue, Jill McElhinny, Barry M. Massie
Journal: Circulation Research (1996)

In patients with congestive heart failure, skeletal muscle is characterized by a smaller proportion of slow-twitch oxidative fibers and reduced oxidative enzyme activity. However, whether these changes result from disuse or occur as a direct consequence of heart failure is unresolved. To address this issue, 18 rats with heart failure 8 weeks after left coronary artery ligation and 13 sham-operated control rats underwent quantification of locomotor activity by a photocell activation technique, measurements of hemodynamics and infarct size, histochemical and morphological analyses of the soleus and plantaris muscles, and Northern analyses of muscle contractile protein and oxidative enzyme mRNA expression. Although the rats with heart failure had elevated left ventricular end-diastolic pressures (24.1±2.6 mm Hg) and a mean infarct size of 35.1±4.1%, activity levels were similar to those found in the sham-operated rats (3849±304 versus 3526±130 counts per hour). With heart failure, there was a significant reduction of type I fibers in the soleus muscle and type IIa fibers in the plantaris muscle, with corresponding increases in intermediate staining of type IIab fibers in both muscles. This was associated with a 17% decrease in citrate synthase activity in both the soleus and plantaris muscles (26.2±1.6 versus 30.7±3.4 and 29.1±2.4 versus 35.7±3.4 μmol/L per minute per gram, respectively [ P &lt;.05]). In the soleus muscle, mRNA for both β-myosin heavy chains and cytochrome C oxidase III (normalized to 18S RNA) was reduced (0.27±0.02 versus 0.65±0.02 and 0.23±0.04 versus 0.64±0.02 U), whereas the messages for IIx and IIb myosin heavy chains were increased. A similar decrease in messages for cytochrome oxidase and the primary myosin isoform was observed in the plantaris muscle. Both soleus β-myosin heavy chain and cytochrome C oxidase expression show significant inverse relationships to left ventricular end-diastolic pressure and infarct size. In contrast, there was no relationship between either β-myosin heavy chain or cytochrome C oxidase expression and locomotor activity. These results indicate that in rats heart failure produces changes in skeletal muscle gene expression at the pretranslational level that cannot be explained by inactivity.
IgE to peanut allergen components: relation to peanut symptoms and pollen sensitization in 8‐year‐olds
Authors: A. Asarnoj, R. Movérare, E. Östblom, M. Poorafshar, G. Lilja, G. Hedlin, M. Van Hage, S. Ahlstedt, M. Wickman
Journal: Allergy (2010)

Allergen-specific IgE testing is often performed with crude peanut extract, but the results may be difficult to interpret because of cross-reactions between peanut and other plant allergens. The aim was to investigate IgE reactivity to peanut allergen components in children from a birch-rich region in relation to pollen sensitization and peanut symptoms.From a birth cohort, clinical parameters were obtained through questionnaires and IgE antibody levels to peanut and birch pollen were measured. Different peanut/birch sensitization phenotypes were defined among 200 selected children. IgE reactivity to peanut and pollen allergen components was analysed using microarray technique.Peanut symptoms were reported in 87% of the children with IgE reactivity to any of the peanut allergens Ara h 1, 2 or 3 but not to Ara h 8 (n = 46) vs 17% of children with IgE reactivity to Ara h 8 but not to Ara h 1, 2 or 3 (n = 23), P < 0.001. Furthermore, symptoms were more severe in children with Ara h 1, 2 or 3 reactivity. Children with IgE reactivity both to Ara h 2 and to Ara h 1 or 3 more often reported peanut symptoms than children with IgE only to Ara h 2 (97%vs 70%, P = 0.016), particularly respiratory symptoms (50%vs 9%, P = 0.002).IgE analysis to peanut allergen components may be used to distinguish between peanut-sensitized individuals at risk of severe symptoms and those likely to have milder or no symptoms to peanut if sensitized to pollen allergens and their peanut homologue allergens.
Navigating the Crossroads of Coronary Artery Disease and Heart Failure
Authors: Mihai Gheorghiade, George Sopko, Leonardo De Luca, Eric J. Velazquez, John D. Parker, Philip F. Binkley, Zygmunt Sadowski, Krzysztof S. Golba, David L. Prior, Jean L. Rouleau, Robert O. Bonow
Journal: Circulation (2006)
The liver in metabolic syndrome
Authors: A. D Smith
Journal: Journal of the Royal Society of Medicine (2005)

In their review article last year, Wilkin and Voss1 made no reference to the potential impact of the metabolic syndrome upon the liver. Non-alcoholic fatty liver disease (NAFLD) should be numbered among the consequences of insulin resistance, hyperinsulinaemia and continued weight gain.2 It encompasses a spectrum of liver injury ranging from uncomplicated macrovesicular steatosis on the one hand, through non-alcoholic steatohepatitis (NASH, i.e. steatosis, ballooning degeneration of hepatocytes, neutrophil infiltration and pericentral pericellular fibrosis) to cirrhosis and liver failure at the opposite extreme. NAFLD is now judged the most likely explanation for non-specific liver test abnormalities among patients referred for evaluation thereof.3 Furthermore, NASH may have been responsible for a substantial proportion of cases of cryptogenic cirrhosis referred for and undergoing orthotopic liver transplantation.4

The diagnosis of NAFLD should be considered in any patient who exhibits one or more components of the metabolic syndrome5 and has abnormal liver tests, demonstrates clinical features of chronic liver disease, or both. As with other complications of the metabolic syndrome the more components that are present, the greater the likelihood that the patient has NAFLD. However, risk factors in and of themselves are not yet reliable predictors of the degree of fibrosis that may be present, and thus the extent of liver dysfunction and/or portal hypertension.2 Therefore, liver biopsy remains an important diagnostic tool among such patients.

In addition to increasing our understanding of the pathophysiology of NAFLD—e.g. which patients with uncomplicated steatosis may develop inflammation and fibrosis—it is vital that the potential impact of NASH and subsequent end-stage liver disease be appreciated and accepted by non-liver physicians. Otherwise, it may yet be the case that the burden of NASH upon liver transplant services will exceed that of chronic hepatitis C virus liver disease.
Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma
Authors: Mark E. Dudley, John R. Wunderlich, James C. Yang, Richard M. Sherry, Suzanne L. Topalian, Nicholas P. Restifo, Richard E. Royal, Udai Kammula, Don E. White, Sharon A. Mavroukakis, Linda J. Rogers, Gerald J. Gracia, Stephanie A. Jones, David P. Mangiameli, Michelle M. Pelletier, Juan Gea-Banacloche, Michael R. Robinson, David M. Berman, Armando C. Filie, Andrea Abati, Steven A. Rosenberg
Journal: Journal of Clinical Oncology (2005)

We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma.Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL) -2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m(2)). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy.Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 +/- 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation.Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.
Dying of excitement
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

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A mutation in the promoter region of the gene encoding the glutamate transporter EAAT2 is associated with increased neurological deterioration after stroke.For neurons, overexcitement is deadly. To avoid this, brain cells must sop up unneeded neurotransmitters from the
Bone metastasis and poor performance status are prognostic factors for survival of carcinoma of unknown primary site in patients treated with systematic chemotherapy
Authors: M. Kodaira, S. Takahashi, S. Yamada, K. Ueda, Y. Mishima, K. Takeuchi, N. Yamamoto, Y. Ishikawa, M. Yokoyama, T. Saotome, Y. Terui, K. Hatake
Journal: Annals of Oncology (2009)
β <sub>1</sub> -Adrenergic Receptor and Sphingosine-1-Phosphate Receptor 1 (S1PR1) Reciprocal Downregulation Influences Cardiac Hypertrophic Response and Progression to Heart Failure
Authors: Alessandro Cannavo, Giuseppe Rengo, Daniela Liccardo, Gennaro Pagano, Carmela Zincarelli, Maria Carmen De Angelis, Roberto Puglia, Elisa Di Pietro, Joseph E. Rabinowitz, Maria Vittoria Barone, Plinio Cirillo, Bruno Trimarco, Timothy M. Palmer, Nicola Ferrara, Walter J. Koch, Dario Leosco, Antonio Rapacciuolo
Journal: Circulation (2013)

The sphingosine-1-phosphate receptor 1 (S1PR1) and β1-adrenergic receptor (β1AR) are G-protein-coupled receptors expressed in the heart. These 2 receptors have opposing actions on adenylyl cyclase because of differential G-protein coupling. Importantly, both of these receptors can be regulated by the actions of G-protein-coupled receptor kinase-2, which triggers desensitization and downregulation processes. Although classic signaling paradigms suggest that simultaneous activation of β1ARs and S1PR1s in a myocyte would simply result in opposing action on cAMP production, in this report we have uncovered a direct interaction between these 2 receptors, with regulatory involvement of G-protein-coupled receptor kinase-2.In HEK (human embryonic kidney) 293 cells overexpressing both β1AR and S1PR1, we demonstrated that β1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a β-adrenergic receptor agonist) treatment. This cross talk between these 2 distinct G-protein-coupled receptors appears to have physiological significance, because they interact and show reciprocal regulation in mouse hearts undergoing chronic β-adrenergic receptor stimulation and in a rat model of postischemic heart failure.We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious β1AR overstimulation in heart failure.
SUblobularcompartmentationofpharmacologicevents (scope): Metabolic fluxes in periportal and pericentral regions of the liver lobule
Authors: Ronald G. Thurman, Frederick C. Kauffman
Journal: Hepatology (1985)

New techniques have been developed employing microlight guides and miniature O2 electrodes which permit metabolic events to be studied noninvasively in periportal and pericentral zones of the liver lobule. These events include O2 uptake, fat and carbohydrate metabolism, monooxygenation and glucuronidation. The lobular distribution of maximal enzyme activities measured by immunohistochemical or microchemical techniques does not always correlate with metabolic flux rates as measured in periportal and pericentral regions with the new noninvasive methods. The region of the liver lobule exhibiting highest metabolic flux rates can be shifted to another region of the lobule by changing the direction of flow from anterograde to retrograde. These data are consistent with the hypothesis that many metabolic pathways (e.g., oxygen, carbohydrate and fat metabolism which are under dynamic short-term regulation) operate below maximal velocity in intact hepatocytes.
Access to Quality
Authors: Jesse D. Schold, Bruce Kaplan, Neale R. Chumbler, Richard J. Howard, Titte R. Srinivas, Linan Ma, Herwig-Ulf Meier-Kriesche
Journal: Journal of the American Society of Nephrology (2005)

Disparities in both access to the kidney transplant waiting list and waiting times for transplant candidates have been extensively documented with regard to ethnicity, gender, socioeconomic factors, and region. However, the issue of access to equivalent quality organs has garnered less attention. The principal aim of this study was to determine whether certain patient populations were more likely to receive lower quality organs. This was a retrospective cohort study of all deceased-donor adult renal transplant recipients in the United States from 1996 to 2002 (n = 45,832). Using previously reported categorization of donor quality (I to V), the propensity of transplant recipients to receive lower-quality kidneys in a cumulative logit model was evaluated. Older patients were progressively more likely to receive lower-quality organs (age > or = 65 yr, odds ratio [OR] = 2.1, P < 0.01) relative to recipients aged 18 to 24 yr. African American and Asian recipients had a greater likelihood of receiving lower-quality organs relative to non-Hispanic Caucasians. Regional allocation networks were highly variable with regard to donor quality. Neither recipient gender (OR = 1.00, P = 0.81) nor patient's primary diagnosis were associated with donor quality. Findings suggest that disparities in the quality of deceased donor kidneys to transplant recipients exist among certain patient groups that have previously documented access barriers. The extent to which these disparities are in line with broad policies of equity and potentially modifiable will have to be examined in the context of allocation policy.