tbuckley/cabot-search huggingface dataset:
Delayed thymocyte development induced by augmented expression of p56lck.
Authors: K M Abraham, S D Levin, J D Marth, K A Forbush, R M Perlmutter
Journal: The Journal of Experimental Medicine (1991)

Accumulating evidence supports the contention that CD4 and CD8 receptor molecules play a critical signaling role during thymocyte development. The lymphocyte-specific protein tyrosine kinase (p56lck), by virtue of its physical association with these surface components, provides a likely candidate for the biochemical signal transducing element required for these effects. To investigate the function of p56lck in T lymphocytes, transgenic mice were produced that carry either the wild-type lck gene or a mutated lck gene encoding a constitutively activated form of p56lck (p56lckF505). Both transgenes were expressed in thymocytes under the control of the lck proximal promoter element. A large set of founder animals was obtained in which steady-state accumulation of lck transgene mRNA directly correlated with transgene copy number, suggesting that this transgene contains a dominant control region. Progeny of these founders exhibited a transgene-dependent dose-related decrease in the production of thymocytes bearing functional antigen receptors. This effect was strictly dependent on p56lck activity, in that both wild-type and mutated versions of the genes induced similar effects with differing efficiencies. Remarkably, even a twofold increase in p56lck abundance was sufficient to substantially disrupt the appearance of functional thymocytes. These results indicate that thymocyte maturation is regulated in part by signals derived from p56lck.
P1-09-05: A 3′UTR Functional Variant in BRCA1: A Predictor of Poor Outcome in Breast Cancer.
Authors: JJ Dorairaj, N Miller, J Newell, MJ Kerin, JB Weidhaas
Journal: Cancer Research (2011)

Abstract Background: MicroRNAs (miRNAs) are class of gene regulators which exert their effects through binding with partial complementarity to sequences in the 3'untranslated region (3'UTR) of the target mRNA. Single nucleotide polymorphisms (SNPs) in the 3'UTR of target mRNA have the potential to disrupt or create new illegitimate miRNA targets and have been associated with cancer predisposition as well as tumor biology. An association between rs8176318 and risk for familial breast and ovarian cancer as well as risk for triple negative breast cancer in African American women has previously been established. We aimed to evaluate the phenotypic effect of rs8176318 in a west of Ireland breast cancer cohort, and also its role as a biomarker of prognosis. Methods: DNA from 727 unselected breast cancer cases and 387 controls were extracted from whole blood and genotyped for rs8176318 in the 3'UTR of the BRCA1 oncogene. The association with disease specific parameters and outcome were evaluated. Results: Overall, there was a significant difference in the distribution of the three genotypes between cases and controls (p=0.035). The dominant variant model was predictive of breast cancer (OR=1.4, 95% CI 1.1−1.8). Fifty-two percent of breast cancer cases had the variant, with similar prevalence between subtypes: Luminal A (279 [54%] of 519 cases), Luminal B (37 [43%] of 85 cases), HER2 (21 [53%] of 40 cases) and triple negative breast cancer (41 [49%] of 83 cases). Comparing the prevalence of the variant within respective subtypes with controls however, Luminal A breast cancer was most strongly associated with rs8176318 (OR=1.5, 95%CI 1.1−1.9). The variant was not significantly associated with disease free survival (DFS) in all cancer cases (Log-rank test=0.084). However, rs8176318 was predictive of a poorer DFS (Log-rank test=0.041) in Luminal A patients with a 10-year DFS of 54% (95% CI 0.4−0.7) and 77% (95%CI 0.7−0.9) for the variant versus the non-variant, respectively. In addition, patients with Stage IV disease had a 6-fold increased risk of carrying the variant (p = 0.035), with 17 (73%) of 23 patients with metastasis at presentation positive for the variant compared to 324 (50%) of 642 patients without metastasis (p=0.034). Luminal A patients with Stage IV disease had a 13-fold risk of carrying the variant (p=0.043) in regression analysis, controlling for all other clinicopathological variables. Similarly, the variant was associated with distant metastasis in Luminal A patients, with 11 (92%) of 12 patients with metastasis positive for the variant compared to 242 (52%) of 463 patients without metastasis (p=0.028). Conclusion: These findings suggest that rs8176318, a variant in the 3'UTR of BRCA1, is a genetic marker for modest breast cancer risk but aggressive tumor biology in breast cancer, and highlights the need for further clinical and biological evaluation of such markers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-09-05.
Prolonged and fractionated right atrial electrograms during sinus rhythm in patients with paroxysmal atrial fibrillation and sick sinus node syndrome
Authors: Muneo Tanigawa, Masahiko Fukatani, Atsushi Konoe, Shojiro Isomoto, Mitsuo Kadena, Kunitake Hashiba
Journal: Journal of the American College of Cardiology (1991)
Administration and Supervision in Laboratory Medicine
Authors: Frances K. Widmann
Journal: JAMA (1989)

Having just become acting chief of a laboratory with 77 employees, I hoped this book would make my task easier. It didn't. No book or article ever does directly address your own specific problems, but textbooks of anatomic pathology offer explicitly applicable descriptive material and differential diagnostic considerations, and clinical pathology texts relate pathophysiology and instrumentation to individual laboratory findings. This book offers capsule generalizations, an overview of individual and group psychology, and a lot of circles and rectangles linked by arrows and lines. The editors have set themselves the task of "bridg[ing] the gap between the theory of management and its application in the clinical laboratory setting." Physicians tend to be suspicious of concepts like "the theory of management," and the 31 chapters by 36 contributors did little to convince me otherwise. Sections that present specific details about topics of limited scope are the most useful. In Part 4,
Value of Echocardiographic Measurement of Left Ventricular Mass in Predicting Cardiovascular Morbid Events in Hypertensive Men
Authors: Paul N. Casale, Richard B. Devereux, Mark Milner, Gerardo Zullo, Gregory A. Harshfield, Thomas G. Pickering, John H. Laragh
Journal: Annals of Internal Medicine (1986)

To assess whether echocardiographic and electrocardiographic detection of left ventricular hypertrophy could predict cardiovascular morbid events in patients with uncomplicated essential hypertension, we followed 140 men for a mean of 4.8 years. Initial echocardiographic measurements of left ventricular mass were normal (< 125 g/m2 body surface area) in 111 patients and revealed hypertrophy in 29 patients. Morbid events occurred in more patients with hypertrophy on echocardiography (7 of 29,4.6/100 patient-years) than with normal ventricular mass (7 of 111,1.4/100 patient-years; p < 0.01). Electrocardiography showed hypertrophy in too few patients to be of predictive value. Multiple logistic regression analysis showed that left ventricular mass index had the highest independent relative risk for future events and that systolic and diastolic pressures and age had slightly lower relative risks. In men with mild uncomplicated hypertension, left ventricular hypertrophy detected by echocardiography identifies patients at high risk for cardiovascular morbid events and is a significant risk factor for future morbid events independent of age, blood pressure, or resting ventricular function.
Increased Ureagenesis and Impaired Nitrogen Use during Infusion of a Synthetic Amino Acid Formula
Authors: Janet L. Smith, Carlos Arteaga, Steven B. Heymsfield
Journal: New England Journal of Medicine (1982)

In a controlled trial conducted to assess the biologic value of High Nitrogen Vivonex, we compared this "elemental" diet with predigested protein--Product MJ7041--and with solid food during eight-day balance periods. Each formula was evaluated in three patients with malabsorption and one without it, by measuring apparent absorption of nitrogen and energy, nitrogen balance, and blood and urinary urea nitrogen. Overall energy and nitrogen absorption in the patients with malabsorption was better with either special diet than with solid food; net intestinal uptake of Vivonex tended to be higher but not consistently so in al patients. However, nitrogen balance differed consistently during the three diets; with solid food and MJ7041, retention of absorbed nitrogen was respectively, nine and 16 times greater than with Vivonex. Moreover, institution of each Vivonex period led to a prompt increase in urea nitrogen--a trend quickly reversed by the alternative diets. Although the mechanism for the impairment of nitrogen use caused by High Nitrogen Vivonex is unknown, its low biologic value and tendency to cause azotemia should be kept in mind.
The anti-tobacco campaign of the Nazis: a little known aspect of public health in Germany, 1933-45
Authors: R. N Proctor
Journal: BMJ (1996)

Historians and epidemiologists have only recently begun to explore the Nazi anti-tobacco movement. Germany had the world's strongest antismoking movement in the 1930s and early 1940s, encompassing bans on smoking in public spaces, bans on advertising, restrictions on tobacco rations for women, and the world's most refined tobacco epidemiology, linking tobacco use with the already evident epidemic of lung cancer. The anti-tobacco campaign must be understood against the backdrop of the Nazi quest for racial and bodily purity, which also motivated many other public health efforts of the era.
Intense Fluorodeoxyglucose Activity in Pulmonary Amyloid Lesions on Positron Emission Tomography
Authors: Justin Kung, Hongming Zhuang, Jian Q. Yu, Paulo S. Duarte, Abass Alavi
Journal: Clinical Nuclear Medicine (2003)

Imaging with F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been widely accepted as an important diagnostic modality in the evaluation of patients with possible cancers. However, FDG is not a tumor-specific tracer and numerous nonmalignant processes can result in increased FDG accumulation. Amyloidosis includes a group of diseases in which 1 or more organ systems in the body accumulates deposits of a substance of proteinaceous nature. We report the detection of an amyloid lesion by FDG-PET in a patient with suspected lung malignancy.
Genomewide genetic association studies in hepatology: The end of searching for the needle in the haystack?
Authors: Claus Hellerbrand, Hermann E. Wasmuth, Kris Kowdley
Journal: Hepatology (2007)

With an overall prevalence of 10-20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an association scan of > 500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P(CCA) = 4.1 × 10(−9)), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 × 10(−7)) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P = 1.4 × 10(−14)) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.
Hypercalcemia in Reticulum Cell Sarcoma Without Hyperparathyroidism or Skeletal Metastases
Authors: FREDERICK R. SINGER
Journal: Annals of Internal Medicine (1973)

A patient with reticulum cell sarcoma and hypercalcemia had a remission of the hypercalcemia after localized radiation therapy. The tumor and hypercalcemia recurred 2 years later. Examination of blood and tumor extract from the patient by a sensitive radioimmunoassay for parathyroid hormone failed to detect the hormone. Tumor extract raised serum calcium when injected into parathyroidectomized mice and caused release of 45Ca from mouse calvaria in vitro. At autopsy the patient had four normal parathyroid glands and no skeletal metastases. The humoral agent responsible for the hypercalcemia in this patient remains to be elucidated.
Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation
Authors: Min Jung Kim, Bum-Joon Park, Young-Sun Kang, Hyoung June Kim, Jae-Hyun Park, Jung Woo Kang, Sang Won Lee, Jung Min Han, Han-Woong Lee, Sunghoon Kim
Journal: Nature Genetics (2003)
Podoplanin-Expressing Cells Derived From Bone Marrow Play a Crucial Role in Postnatal Lymphatic Neovascularization
Authors: Ji Yoon Lee, Changwon Park, Yong Pil Cho, Eugine Lee, Hyongbum Kim, Pilhan Kim, Seok H. Yun, Young-sup Yoon
Journal: Circulation (2010)

Background— Emerging evidence has suggested a contribution of bone marrow (BM) cells to lymphatic vessel formation; however, the exact phenotype of the cells with lymphatic endothelial progenitor cell function has yet to be identified. Here, we investigate the identity of BM-derived lymphatic endothelial progenitor cells and their role in lymphatic neovascularization. Methods and Results— Culture of BM-mononuclear cells in the presence of vascular endothelial growth factors A and C and endothelial growth factor resulted in expression of lymphatic endothelial cell markers. Among these cells, podoplanin + cells were isolated by magnetic-activated cell sorting and characterized by fluorescence-activated cell sorter analysis and immunocytochemistry. These podoplanin + cells highly express markers for lymphatic endothelial cells, hematopoietic lineages, and stem/progenitor cells; on further cultivation, they generate lymphatic endothelial cells. We further confirmed that podoplanin + cells exist in small numbers in BM and peripheral blood of normal mice but are significantly (15-fold) augmented on lymphangiogenic stimuli such as tumor implantation. Next, to evaluate the potential of podoplanin + cells for the formation of new lymphatic vessels in vivo, we injected culture-isolated or freshly isolated BM-derived podoplanin + cells into wound and tumor models. Immunohistochemistry demonstrated that the injected cells were incorporated into the lymphatic vasculature, displayed lymphatic endothelial cell phenotypes, and increased lymphatic vascular density in tissues, suggesting lymphvasculogenesis. Podoplanin + cells also expressed high levels of lymphangiogenic cytokines and increased proliferation of lymphatic endothelial cells during coculture, suggesting a lymphangiogenic or paracrine role. Conclusions— Our results provide compelling evidence that BM-derived podoplanin + cells, a previously unrecognized cell type, function as lymphatic endothelial progenitor cells and participate in postnatal lymphatic neovascularization through both lymphvasculogenesis and lymphangiogenesis.
The defect in Fas mRNA expression in MRL/lpr mice is associated with insertion of the retrotransposon, ETn.
Authors: J L Chu, J Drappa, A Parnassa, K B Elkon
Journal: The Journal of Experimental Medicine (1993)

Fas is a cell surface protein of the tumor necrosis factor receptor, nerve growth factor receptor, CD40 family, and is involved in the control of lymphocyte apoptosis. A mutation in the Fas gene in MRL/lpr mice results in massive lymphoproliferation (lpr) and accelerated autoimmunity. To further study the nature of this defect, Fas mRNA expression was evaluated by reverse transcriptase polymerase chain reaction as well as by Northern blotting. These studies revealed that the wild-type Fas message was produced at approximately 10-fold lower levels in the lpr compared with the ++ substrain of MRL mice. In addition to the wild-type transcript, lpr mice also synthesized chimeric transcripts containing an insertion of the early retrotransposon (ETn). Molecular cloning and nucleotide sequencing of a Fas-ETn chimeric cDNA suggested that the striking reduction in wild-type Fas mRNA levels and the presence of aberrant transcripts in MRL/lpr mice are most likely explained by the insertion of the ETn retrotransposon into an intron of the Fas gene and induction of alternative splicing involving the 5' ETn long terminal repeat.
Contribution of hepatic adenosine A1 receptors to renal dysfunction associated with acute liver injury in rats
Authors: Zhi Ming, Yi‐Jun Fan, Xi Yang, W. Wayne Lautt
Journal: Hepatology (2006)

Acute liver injury is associated with renal insufficiency, whose mechanism may be related to activation of the hepatorenal reflex. We previously showed that intrahepatic adenosine is involved in activation of the hepatorenal reflex to restrict urine production in both healthy rats and in rats with cirrhosis. The aim of the present study was to test the hypothesis that activation of intrahepatic adenosine receptors is involved in the pathogenesis of the renal insufficiency seen in acute liver injury. Acute liver injury was induced by intraperitoneal injection of thioacetamide (TAA, 500 mg/kg) in rats. The animals were instrumented 24 hours later to monitor systemic, hepatic, and renal circulation and urine production. Severe liver injury developed following TAA insult, which was associated with renal insufficiency, as demonstrated by decreased (∼25%) renal arterial blood flow, a lower (∼30%) glomerular filtration rate, and decreased urine production. Further, the increase in urine production following volume expansion challenge was inhibited. Intraportal, but not intravenous, administration of a nonselective adenosine receptor antagonist, 8-phenyltheophylline, improved urine production. To specify receptor subtype, the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an adenosine A1 receptor antagonist) and 3,7-dimethyl-1-propargylxanthine (DMPX, an adenosine A2 receptor antagonist) were compared. Intraportal but not intravenous administration of DPCPX greatly improved impaired renal function induced by acute liver injury, and this beneficial effect was blunted in rats with liver denervation. In contrast, neither intraportal nor intravenous administration of DMPX showed significant improvement in renal function. In conclusion, an activated hepatorenal reflex, triggered by intrahepatic adenosine A1 receptors, contributed to the pathogenesis of the water and sodium retention associated with acute liver injury. (HEPATOLOGY 2006;44:813–822.)
Quality of life in patients undergoing small intestinal transplantation
Authors: C. Pither, A. Wiles, A. Butler, H. Tinknell, S. Duncan, J. Woodward, N. Jamieson, B. Chukualim, M. Manaligod, S. Gabe, S. Middleton
Journal: Gut (2011)

<h3>Introduction</h3> Intestinal transplantation is currently considered for patients with irreversible intestinal failure who develop life threatening complications of home parenteral nutrition (HPN) or who have extensive intra-abdominal disease requiring evisceration Thus far quality of life (QOL) has not been used as an indication for transplantation but as post-operative survival improves this may be considered appropriate in the future if improvements in QOL can be obtained compared with HPN. Previous studies suggest improvement in some aspects in carefully selected patients.1–3 Our latest 2 year survival rates are 100% (non-oncological) and 98% (oncological). We looked at changes in the QOL of this cohort of recent transplantations <h3>Aims</h3> To assess the quality of life of patients requiring small intestinal transplantation using the SF 36 tool. <h3>Methods</h3> 18 patients completed the questionnaire as part of the transplant assessment and subsequently at 6 monthly intervals. Data was scored using validated criteria for each of eight functions: physical function, role functioning-physical, role functioning- emotional, energy/fatigue, emotional wellbeing, social functioning, pain and general health. <h3>Results</h3> A total number of 36 datasets were analysed, 19 preoperatively (6 male, 13 female) and 17 post-operatively from a total of 8 patients (4 male, 4 female). Paired scores pre and postoperatively from 6 patients (3 male, 3 female) were also analysed. The grouped data showed a significant improvement in physical function p=0.05* social function p=0.01* and general health p=0.05*. Other function scores were very similar. General health was the only modality showing significant improvement in the paired data p=0.03**. When the data was analysed for each patient, 2 out of 6 patients had significantly better overall scores after the transplant, p=0.02**, p=0.007**. *Mann–Whitney U test ** Wilcoxon signed rank <h3>Conclusion</h3> QOL on HPN is impaired45 and declines over time. Our short term survival is approaching that of HPN. Some aspects of QOL can be improved with transplantation but others do not seem to improve. If QOL is to be a factor in the consideration of patients for intestinal or multivisceral transplantation it will be important to look at each individual quality of life aspect as some seem to be more likely to improve than others. Longer term studies are required
Reduced Inflammatory Response to Plasmid DNA Vectors by Elimination and Inhibition of Immunostimulatory CpG Motifs
Authors: Nelson S. Yew, Hongmei Zhao, I-Huan Wu, Antonius Song, Jennifer D. Tousignant, Malgorzata Przybylska, Seng H. Cheng
Journal: Molecular Therapy (2000)

An inflammatory response is invariably associated with administration of gene transfer complexes composed of cationic lipids and plasmid DNA (pDNA). In the lung, an influx of neutrophils and elevated levels of several proinflammatory cytokines such as TNF-α, IFN-γ, IL-6, and IL-12 characterize this dose-dependent response. The induction of these cytokines was shown previously to be due in part to the presence of unmethylated CpG dinucleotides in the bacterially derived pDNA. We have eliminated 270 of 526 CpG dinucleotides in a reporter plasmid (pCFA-CAT) and tested the inflammatory response to cationic lipid:pDNA complexes containing the modified vector (pGZA-CAT) after intravenous (iv) or intranasal (i.n.) delivery into BALB/c mice. Compared to the unmodified vector, the CpG-reduced pGZA-CAT was found to be significantly less immunostimulatory, as the levels of IL-12, IFN-γ, and IL-6 in the serum 24 h after iv delivery were reduced by 40 to 75%. Similar reductions in cytokine levels were also observed in the bronchoalveolar lavage fluids (BALF) after i.n. administration, while the levels of reporter gene expression were not affected by the modifications. We have also investigated known inhibitors of the CpG signaling pathways in order to decrease the inflammatory response. Two such inhibitors, chloroquine and quinacrine, greatly reduced the induction of IL-12 from mouse spleen cells in vitro and inhibited cytokine production in the lung by approximately 50% without affecting gene expression. These results illustrate that use of a less immunostimulatory pDNA vector or inhibitors of CpG immunostimulation can reduce significantly the toxicity associated with cationic lipid:pDNA complexes thereby increasing the therapeutic index of this synthetic gene transfer vector.