tbuckley/cabot-search huggingface dataset:
Obesity and Survival Among Black Women and White Women 35 to 64 Years of Age at Diagnosis With Invasive Breast Cancer
Authors: Yani Lu, Huiyan Ma, Kathleen E. Malone, Sandra A. Norman, Jane Sullivan-Halley, Brian L. Strom, Polly A. Marchbanks, Robert Spirtas, Ronald T. Burkman, Dennis Deapen, Suzanne G. Folger, Michael S. Simon, Michael F. Press, Jill A. McDonald, Leslie Bernstein
Journal: Journal of Clinical Oncology (2011)

To evaluate the effect of obesity on survival among black women and white women with invasive breast cancer and to determine whether obesity explains the poorer survival of black women relative to white women.We observed 4,538 (1,604 black, 2,934 white) women who were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. Multivariate Cox regression models were used to examine the effect of body mass index (BMI, in kilograms per square meter) 5 years before diagnosis on risk of death from any cause and from breast cancer.During a median of 8.6 years of follow-up, 1,053 women died (519 black, 534 white), 828 as a result of breast cancer (412 black, 416 white). Black women were more likely to die than white women (multivariate-adjusted relative risk [RR], 1.33; 95% CI, 1.16 to 1.53). Compared with women with BMI of 20 to 24.9 kg/m(2), those who were obese (BMI ≥ 30 kg/m(2)) had a greater risk of all-cause mortality (RR, 1.23; 95% CI, 1.04 to 1.47) and breast cancer-specific mortality (RR, 1.20; 95% CI, 0.99 to 1.46). These associations were observed among white women (all-cause RR, 1.54; 95% CI, 1.21 to 1.96; breast cancer RR, 1.46; 95% CI, 1.11 to 1.92), but not among black women (all-cause RR, 1.03; 95% CI, 0.81 to 1.29; breast cancer RR, 1.02; 95% CI, 0.79 to 1.33).Obesity may play an important role in mortality among white but not black patients with breast cancer. It is unlikely that differences in obesity distributions between black women and white women account for the poorer survival of black women.
THE EFFECT OF ANTITESTICULAR SERUM ON THE ENHANCEMENT VALUE OF TESTICLE EXTRACT
Authors: F. Duran-Reynals
Journal: The Journal of Experimental Medicine (1932)

The experiments reported here show that the infection-enhancing factor of testicle extract is neutralized in vitro by an antiserum against homologous testicle extract. An antiserum developed against a testicle extract of one species does not influence the enhancing and spreading factor of the extract from another species. Rabbits immunized against testicle extract do not exhibit any alteration in the spreading or enhancing effect of extracts employed later, even when the testicle extract used is from the same species as that employed for the immunization. Whether the in vitro inactivation of the active factor is a specific neutralization, or is the result of adsorption of the factor on the flocculate formed, has not been definitely determined. The fact that there is no neutralization in vivo, and that the antiserum acts only on extracts from the same species, when definite flocculation takes place, tends to emphasize the probability that the neutralization is not a direct one, but is incidental to the flocculation mentioned.
Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of αCaMKII inhibitory phosphorylation
Authors: Geeske M van Woerden, Karen D Harris, Mohammad Reza Hojjati, Richard M Gustin, Shenfeng Qiu, Rogerio de Avila Freire, Yong-hui Jiang, Ype Elgersma, Edwin J Weeber
Journal: Nature Neuroscience (2007)
Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden
Authors: John C O'Leary, Qingyou Li, Paul Marinec, Laura J Blair, Erin E Congdon, Amelia G Johnson, Umesh K Jinwal, John Koren, Jeffrey R Jones, Clara Kraft, Melinda Peters, Jose F Abisambra, Karen E Duff, Edwin J Weeber, Jason E Gestwicki, Chad A Dickey
Journal: Molecular Neurodegeneration (2010)

It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection.Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced.Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.
Exercise responses in patients with an enzyme deficiency in the mitochondrial respiratory chain
Authors: JM Bogaard, HF Busch, HR Scholte, H Stam, A Versprille
Journal: European Respiratory Journal (1988)

Responses to exercise were obtained in six patients with a biochemically diagnosed enzyme deficiency at the level of NADH-CoQ reductase. The responses were compared with those of a control group, consisting of fourteen patients with inexplicable dyspnoea or muscle pain during exercise, for which no firm diagnosis could be established and of which the exercise responses were in the normal range. Metabolic, ventilatory and cardiological variables such as oxygen uptake (VO2), minute ventilation (VE), respiratory exchange ratio (R), heart rate (HR) and difference in blood lactate or base-excess (BE) between rest and maximal workload were measured during cycle ergometry from samples obtained in the last minutes of four minute periods, in which the load increased stepwise by 30 W per four minutes. The threshold of lactate metabolism (Tlact) was assumed to be equal to the threshold determined both by the VO2 at which the VE versus VO2 response started to deviate from a straight line and the ventilatory equivalent for oxygen (VE/VO2) showed a minimum (Tvent), Tvent was estimated from the mean of these values, obtained by linear and parabolic regression analysis respectively. In the patient group, mean values for symptom limited maximal VO2 (VO2,max,sl; % of VO2,max,ref), Tvent (% of VO2,max,ref) and R at maximal workload were 43, 17 and 1.23 against 85, 47 and 1.06 for the same variables in the control group, respectively. The differences were highly significant (p less than 0.001; p less than 0.005 for mean R difference). Mean maximal HR and mean change in blood lactate or BE were not significantly different in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Platelets stimulate expression of endothelin mRNA and endothelin biosynthesis in cultured endothelial cells.
Authors: E H Ohlstein, B L Storer, J A Butcher, C Debouck, G Feuerstein
Journal: Circulation Research (1991)

Modulation of the biosynthesis of the vasoconstrictor peptide endothelin was studied in cultured endothelial cells. Immunoreactive endothelin (irET) levels were significantly elevated in conditioned medium from bovine pulmonary artery endothelial (BPAE) or human umbilical vein endothelial cells when coincubated with washed human platelets. Platelets (approximately 200,000 cells/microliters) enhanced irET levels approximately 250% over basal levels. Stimulation of irET levels in BPAE cell-conditioned medium by platelets was time and platelet number dependent. Platelets, as well as thrombin and transforming growth factor-beta 1, stimulated the expression of preproendothelin-1 mRNA in a time-dependent manner. Coincubation of low doses of thrombin (0.1 unit/ml) and subthreshold concentrations of platelets with BPAE cells resulted in a further enhancement of irET levels in conditioned medium. Platelet-mediated stimulation of irET production was not significantly affected by indomethacin (1 microM) or the platelet-activating factor receptor antagonist WEB 2086 (1 microM); however, coincubation of endotoxin (100 ng/ml) with platelets and BPAE cells resulted in significantly higher levels of irET. Whether direct contact or adhesion between platelets and endothelial cells is necessary for stimulating irET release was studied by separating platelets from BPAE cells with a 0.4 microns permeable membrane. Under these conditions, platelets still produced significant elevations (approximately 190% over basal levels) in irET levels in BPAE cell-conditioned medium. In addition, platelet-free buffer from agonist-induced platelet aggregation also significantly enhanced irET production (200% over basal values). These data indicate that a platelet-derived regulatory factor can induce the biosynthesis of endothelin from cultured endothelial cells and also suggest that platelets might play a role in vasomotor regulation via a novel intercellular interaction with the endothelium.
Regulation of β-catenin by t-DARPP in upper gastrointestinal cancer cells
Authors: Bhavatarini Vangamudi, Shoumin Zhu, Mohammed Soutto, Abbes Belkhiri, Wael El-Rifai
Journal: Molecular Cancer (2011)

Abstract Background Truncated dopamine and cyclic-AMP-regulated phosphoprotein (t-DARPP) is frequently overexpressed in gastrointestinal malignancies. In this study, we examined the role of t-DARPP in regulating β-catenin. Results The pTopFlash construct that contains multiple TCF/LEF-binding sites was used as a measure of β-catenin/TCF transcription activity. Gastric (AGS, MKN28) and esophageal (FLO-1) adenocarcinoma cancer cell lines that lack t-DARPP expression were utilized to establish stable and transient in vitro expression models of t-DARPP. The expression of t-DARPP led to a significant induction of the pTOP reporter activity, indicative of activation of β-catenin/TCF nuclear signaling. Immunofluorescence assays supported this finding and showed accumulation and nuclear translocation of β-catenin in cells expressing t-DARPP. These cells had a significant increase in their proliferative capacity and demonstrated up-regulation of two transcription targets of β-catenin/TCF: Cyclin D1 and c-MYC. Because phosphorylated GSK-3β is inactive and loses its ability to phosphorylate β-catenin and target it towards degradation by the proteasome, we next examined the levels of phospho-GSK-3β. These results demonstrated an increase in phospho-GSK-3β and phospho-AKT. The knockdown of endogenous t-DARPP in MKN45 cancer cells demonstrated a reversal of the signaling events. To examine whether t-DARPP mediated GSK-3β phosphorylation in an AKT-dependent manner, we used a pharmacologic inhibitor of PI3K/AKT, LY294002, in cancer cells expressing t-DARPP. This treatment abolished the phosphorylation of AKT and GSK-3β leading to a reduction in β-catenin, Cyclin D1, and c-MYC protein levels. Conclusions Our findings demonstrate, for the first time, that t-DARPP regulates β-catenin/TCF activity, thereby implicating a novel oncogenic signaling in upper gastrointestinal cancers.
HLA-DQA1–HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
Authors: Graham A Heap, Michael N Weedon, Claire M Bewshea, Abhey Singh, Mian Chen, Jack B Satchwell, Julian P Vivian, Kenji So, Patrick C Dubois, Jane M Andrews, Vito Annese, Peter Bampton, Martin Barnardo, Sally Bell, Andy Cole, Susan J Connor, Tom Creed, Fraser R Cummings, Mauro D'Amato, Tawfique K Daneshmend, Richard N Fedorak, Timothy H Florin, Daniel R Gaya, Emma Greig, Jonas Halfvarson, Alisa Hart, Peter M Irving, Gareth Jones, Amir Karban, Ian C Lawrance, James C Lee, Charlie Lees, Raffi Lev-Tzion, James O Lindsay, John Mansfield, Joel Mawdsley, Zia Mazhar, Miles Parkes, Kirstie Parnell, Timothy R Orchard, Graham Radford-Smith, Richard K Russell, David Reffitt, Jack Satsangi, Mark S Silverberg, Giacomo C Sturniolo, Mark Tremelling, Epameinondas V Tsianos, David A van Heel, Alissa Walsh, Gill Watermeyer, Rinse K Weersma, Sebastian Zeissig, Jamie Rossjohn, Arthur L Holden, Tariq Ahmad
Journal: Nature Genetics (2014)
Targeted expression of transforming growth factor-beta 1 in intracardiac grafts promotes vascular endothelial cell DNA synthesis.
Authors: G Y Koh, S J Kim, M G Klug, K Park, M H Soonpaa, L J Field
Journal: Journal of Clinical Investigation (1995)

Intracardiac grafts comprised of genetically modified skeletal myoblasts were assessed for their ability to effect long-term delivery of recombinant transforming growth factor-beta (TGF-beta) to the heart. C2C12 myoblasts were stably transfected with a construct comprised of an inducible metallothionein promoter fused to a modified TGF-beta 1 cDNA. When cultured in medium supplemented with zinc sulfate, cells carrying this transgene constitutively secrete active TGF-beta 1. These genetically modified myoblasts were used to produce intracardiac grafts in syngeneic C3Heb/FeJ hosts. Viable grafts were observed as long as three months after implantation, and immunohistological analyses of mice maintained on water supplemented with zinc sulfate revealed the presence of grafted cells which stably expressed TGF-beta 1. Regions of apparent neovascularization, as evidenced by tritiated thymidine incorporation into vascular endothelial cells, were observed in the myocardium which bordered grafts expressing TGF-beta 1. The extent of vascular endothelial cell DNA synthesis could be modulated by altering dietary zinc. Similar effects on the vascular endothelial cells were not seen in mice with grafts comprised of nontransfected cells. This study indicates that genetically modified skeletal myoblast grafts can be used to effect the local, long-term delivery of recombinant molecules to the heart.
Molecular Profiling Reveals Low- and High-Grade Forms of Primary Melanoma
Authors: Katja Harbst, Johan Staaf, Martin Lauss, Anna Karlsson, Anna Måsbäck, Iva Johansson, Pär-Ola Bendahl, Johan Vallon-Christersson, Therese Törngren, Henrik Ekedahl, Jürgen Geisler, Mattias Höglund, Markus Ringnér, Lotta Lundgren, Karin Jirström, Håkan Olsson, Christian Ingvar, Åke Borg, Hensin Tsao, Göran Jönsson
Journal: Clinical Cancer Research (2012)

For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84-8.59), and overall (HR = 3.66; 95% CI, 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.
High prevalence of cigarette smoking in patients with palmoplantar pustulosis
Authors: C.J. O'Doherty
Journal: British Journal of Dermatology (1984)

Journal Article High prevalence of cigarette smoking in patients with palmoplantar pustulosis Get access C.J. O'Doherty C.J. O'Doherty University Department of Dermatology, Royal Infirmary, Edinburgh Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 111, Issue s26, 1 July 1984, Page 41, https://doi.org/10.1111/j.1365-2133.1984.tb05269.x Published: 01 July 1984
Deletion of the von Hippel–Lindau gene in pancreatic β cells impairs glucose homeostasis in mice
Authors: James Cantley, Colin Selman, Deepa Shukla, Andrey Y. Abramov, Frauke Forstreuter, Miguel A. Esteban, Marc Claret, Steven J. Lingard, Melanie Clements, Sarah K. Harten, Henry Asare-Anane, Rachel L. Batterham, Pedro L. Herrera, Shanta J. Persaud, Michael R. Duchen, Patrick H. Maxwell, Dominic J. Withers
Journal: Journal of Clinical Investigation (2008)

Defective insulin secretion in response to glucose is an important component of the β cell dysfunction seen in type 2 diabetes. As mitochondrial oxidative phosphorylation plays a key role in glucose-stimulated insulin secretion (GSIS), oxygen-sensing pathways may modulate insulin release. The von Hippel–Lindau (VHL) protein controls the degradation of hypoxia-inducible factor (HIF) to coordinate cellular and organismal responses to altered oxygenation. To determine the role of this pathway in controlling glucose-stimulated insulin release from pancreatic β cells, we generated mice lacking Vhl in pancreatic β cells (βVhlKO mice) and mice lacking Vhl in the pancreas (PVhlKO mice). Both mouse strains developed glucose intolerance with impaired insulin secretion. Furthermore, deletion of Vhl in β cells or the pancreas altered expression of genes involved in β cell function, including those involved in glucose transport and glycolysis, and isolated βVhlKO and PVhlKO islets displayed impaired glucose uptake and defective glucose metabolism. The abnormal glucose homeostasis was dependent on upregulation of Hif-1α expression, and deletion of Hif1a in Vhl-deficient β cells restored GSIS. Consistent with this, expression of activated Hif-1α in a mouse β cell line impaired GSIS. These data suggest that VHL/HIF oxygen-sensing mechanisms play a critical role in glucose homeostasis and that activation of this pathway in response to decreased islet oxygenation may contribute to β cell dysfunction.
Intestinal absorption of sucrose in man: interrelation of hydrolysis and monosaccharide product absorption.
Authors: G M Gray, F J Ingelfinger
Journal: Journal of Clinical Investigation (1966)

Disaccharides are hydrolyzed by their specific enzymes present in the intestinal mucosa (1-3).Although some current textbooks still state that these enzymes are secreted into the intestinal lu- men (4-7), the concentrations of monosaccharide products free in intestinal contents during disac- charide absorption in vitro (8-10) have been found insufficient to support the concept of intraluminal hydrolysis.In addition, the low disaccharidase activity of intestinal contents during the absorp- tion process in vivo (11-13) strongly suggests that the disaccharide either enters the cell before being hydrolyzed or else is hydrolyzed at the cell surface by mucosa-bound enzyme.The released monosaccharide products presumedly are then transported across the intestinal cell (8, 14, 15).Little information is available that relates disac- charide hydrolysis to absorption of the component monosaccharides.Wilson and Vincent (14) com- mented on the accumulation of monosaccharides in the mucosal medium during the process of disac- charide absorption in hamster gut sac preparations, and Dahlqvist and Thomson have reported that large amounts of free fructose accumulate intraluminally during sucrose absorption in the intact rat (16).Despite these findings in animals, Dahlqvist and Borgstr6m found little free intra- luminal monosaccharides during the process of disaccharide absorption in man (12).It was re- cently demonstrated, however, that appreciable
The capillary plexus in the gas exchange zone of human neonatal lung: an ultrastructural study.
Authors: J C Dornan, C Meban
Journal: Thorax (1985)

The structure of the capillary plexus in the gas exchange zone in the lungs of five neonates was investigated by electron microscopy and cytochemical techniques. The results show that the capillaries associated with the terminal respiratory saccules are narrow and that they generally possess two to three endothelial cells per cross section. "Seamless" and protoplasmic capillaries were not observed. A capillary plexus was located on either side of each intersaccular septum and the mesh size of this plexus was relatively large. The gas diffusion pathway in the neonatal lung was found to be very short (mean 1.84 micron). It is suggested that the layer of periodate reactive material lining the luminal surfaces of the capillary endothelial cells may have important functions in vivo.
Chronic inflammatory rheumatic diseases in black Zimbabweans.
Authors: S K Lutalo
Journal: Annals of the Rheumatic Diseases (1985)

The pattern of chronic inflammatory rheumatic diseases seen in 52 black Zimbabweans was determined. These diseases constituted 2% of all treatable chronic endemic medical diseases registered around Gweru City. Rheumatoid arthritis (RA) and gout were the commonest, 38.8% and 28.8% of the total respectively. Systemic lupus erythematosus (SLE), polymyositis, progressive systemic sclerosis, mixed connective tissue disease, ankylosing spondylitis, and Reiter's diseases were seen less frequently. While the rarity of ankylosing spondylitis was not surprising, that of SLE was striking. RA seen in Zimbabwe was as severe as in East Africa, with a mean age of onset of 43.6 (SD 9.6) years, mean ESR 67 (SD 33) mm/h, seropositivity 78%, subcutaneous nodules 10%, and overall deformities in 35% of all cases. Gout was as seen elsewhere, with a mean age of onset 41.5 (SD 7.95) years, M:F ratio 6.5:1, mean male serum uric acid 10.8 (SD 2.69) mg/dl (0.64 +/- 0.16 mmol/l). Alcohol as a precipitating and aggravating factor was supported by a high mean drunkenness score of 10.3 (SD 3.89) out of a maximum of 17. Unawareness and underdiagnosis of these diseases are still likely problems in this part of the world.