tbuckley/cabot-search huggingface dataset:
Targeting Aberrant PI3K/Akt Activation by PI103 Restores Sensitivity to TRAIL-Induced Apoptosis in Neuroblastoma
Authors: Daniela Opel, Ivonne Naumann, Maxi Schneider, Daniela Bertele, Klaus-Michael Debatin, Simone Fulda
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Because we recently identified Akt activation as a novel poor prognostic indicator in neuroblastoma, we investigated whether phosphoinositide 3′-kinase (PI3K) inhibition sensitizes neuroblastoma cells for TRAIL-induced apoptosis. Experimental Design: The effect of pharmacological or genetic inhibition of PI3K or mTOR was analyzed on apoptosis induction, clonogenic survival, and activation of apoptosis signaling pathways in vitro and in a neuroblastoma in vivo model. The functional relevance of individual Bcl-2 family proteins was examined by knockdown or overexpression experiments. Results: The PI3K inhibitor PI103 cooperates with TRAIL to synergistically induce apoptosis (combination index &amp;lt; 0.1), to suppress clonogenic survival, and to reduce tumor growth in a neuroblastoma in vivo model. Similarly, genetic silencing of PI3K significantly increases TRAIL-mediated apoptosis, whereas genetic or pharmacological blockage of mTOR fails to potentiate TRAIL-induced apoptosis. Combined treatment with PI103 and TRAIL enhances cleavage of Bid and the insertion of tBid into mitochondrial membranes, and reduces phosphorylation of BimEL. Additionally, PI103 decreases expression of Mcl-1, XIAP, and cFLIP, thereby promoting Bax/Bak activation, mitochondrial perturbations, and caspase-dependent apoptosis. Knockdown of Bid or Noxa or overexpression of Bcl-2 rescues cells from PI103- and TRAIL-induced apoptosis, whereas Mcl-1 silencing potentiates apoptosis. Bcl-2 overexpression also inhibits cleavage of caspase-3, caspase-8, and Bid pointing to a mitochondria-driven feedback amplification loop. Conclusions: PI103 primes neuroblastoma cells for TRAIL-induced apoptosis by shifting the balance toward proapoptotic Bcl-2 family members and increased mitochondrial apoptosis. Thus, PI3K inhibitors represent a novel promising approach to enhance the efficacy of TRAIL-based treatment protocols in neuroblastoma. Clin Cancer Res; 17(10); 3233–47. ©2011 AACR.
Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.
Authors: T Nesbitt, T M Coffman, R Griffiths, M K Drezner
Journal: Journal of Clinical Investigation (1992)

Although deranged phosphate transport is the fundamental abnormality in X-linked hypophosphatemic (XLH) rickets, it remains unknown if this defect is the consequence of an intrinsic kidney abnormality or aberrant production of a humoral factor. To discriminate between these possibilities, we examined phosphate homeostasis in normal and Hyp mice, subjected to renal crosstransplantation. We initially evaluated the effects of uninephrectomy on the indices of phosphate metabolism that identify the mutant biochemical phenotype. No differences were found in the serum phosphorus concentration, fractional excretion of phosphate (FEP), or tubular reabsorption of phosphate per milliliter of glomerular filtrate (TRP) in uninephrectomized normal and Hyp mice, compared with sham-operated controls. Subsequently, single kidneys from normal or Hyp mice were transplanted into normal and Hyp mouse recipients. Normal mice transplanted with normal kidneys and Hyp mice engrafted with mutant kidneys exhibited serum phosphorus, FEP, and TRP no different from those of uninephrectomized normal and Hyp mice, respectively. However, engraftment of normal kidneys in Hyp mice and mutant kidneys in normal mice affected neither serum phosphorus (4.69 +/- 0.31 and 8.25 +/- 0.52 mg/dl, respectively) nor FEP and TRP of the recipients. These data indicate that the Hyp mouse phenotype is neither corrected nor transferred by renal transplantation. Further, they suggest that the phosphate transport defect in Hyp mice, and likely X-linked hypophosphatemia, is the result of a humoral factor, and is not an intrinsic renal abnormality.
Oral immunotherapy with type V collagen in idiopathic pulmonary fibrosis
Authors: David S. Wilkes, Terrence Chew, Kevin R. Flaherty, Sarah Frye, Kevin F. Gibson, Naftali Kaminski, Michael J. Klemsz, Wade Lange, Imre Noth, Katia Rothhaar
Journal: European Respiratory Journal (2015)

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. IPF appears to be heterogeneous in pathobiology with ∼40% of IPF patients found to have elevated levels of circulating antibodies to the autoantigen type V collagen (col(V)). Following a targeted, precision medicine approach, we conducted a phase 1 study to test the safety and explore potential efficacy of IW001, a col(V) oral immunotherapeutic developed to treat antibody-positive IPF patients. We divided 30 antibody-positive IPF patients into three cohorts for daily dosing over a 24-week period. All patients completed treatment without serious adverse events, acute exacerbations or IPF-related hospitalisations. A decline in lung function occurred in the lowest-dose cohort that was comparable to that reported in placebo arms of published IPF trials. In contrast, the highest-dose cohort showed a trend toward stabilisation of forced vital capacity and matrix metalloproteinase 7, and a reduction in binding of C1q to anti-col(V) antibodies. IW001 may modulate the immune response to col(V) and may represent a new therapeutic for col(V)- reactive IPF patients.
Oral Contraceptives and Physiological Variables
Authors: Leon D. Ostrander
Journal: JAMA (1980)

Physiological variables were compared among women who had never used oral contraceptives, past users, and current users. Randomly selected subjects were aged 30 to 59 years. Blood was sampled for determination of blood glucose, serum cholesterol and triglyceride, and plasma insulin concentration. Summed postchallenge glucose and insulin values were used in analyses to represent the magnitude of response. Contours of glucose and insulin curves were represented by single numerical variables termed "G-CON" and "I-CON." Current users of oral contraceptives had significantly higher values of G-CON, I-CON, triglyceride, and systolic blood pressure than women who never used oral comtraceptives. Current users also had significantly higher levels of summed glucose, G-CON, and I-CON than former users. Use of currently prescribed oral contraceptives is associated with adverse physiological changes that are reversible after discontinuing such use.Blood levels were measured in a total of 270 randomly selected women, aged 30-59 years, of glucose, serum cholesterol, serum triglyceride, and plasma insulin concentrations to determine the effects of oral contraceptive (OC) usage on these physiological parameters. The women studied were classified as past users, current users, and never users. In addition, numerical values were calculated to represent contours of the postchallenge glucose and insulin level (G-CON and I-CON, respectively). 20 women were current users, 103 were former users, and 147 were never users. Current users had higher mean levels of all variables than women who had never used OCs, and differences were statistically significant for G-CON, I-CON, triglyceride, and systolic blood pressure (BP). Current users also had higher mean variables than former users (except for diastolic BP), and differences were significant for postchallenge blood glucose, G-CON, I-CON. Former users had a significantly higher mean diastolic BP level than women who had never used OCs, but were similar with respect to other variables to the other 2 groups. The findings indicate that formulations of OCs commonly prescribed in this population sample had measurable metabolic effects.
Regulation of hepatic triglyceride synthesis in diabetic rats.
Authors: V K Murthy, J C Shipp
Journal: Journal of Clinical Investigation (1981)

The syntheses of triglyceride and its precursors were increased when liver homogenates of ketotic diabetic rats were incubated with [U-14C]-glycero 3-phosphate and cofactors. Triolein sonicates produced a concentration-dependent inhibition of the synthesis of both diglyceride and triglyceride, whereas monoolein sonicates had no effect. Rat serum very low density lipoproteins, like triolein sonicates, inhibited the synthesis of diglyceride and triglyceride. Furthermore, the intracellular form of very low density lipoproteins, namely nascent very low density lipoproteins, also inhibited the synthesis of diglyceride and triglyceride. A higher apparent I50 (concentration of inhibitor that produces 50% inhibition of activity) was observed in liver homogenates of ketotic diabetic rats for inhibition of triglyceride or diglyceride synthesis by triolein sonicates, serum very low density lipoproteins, high density lipoproteins, and nascent very low density lipoproteins. Insulin treatment of the diabetic rats reversed the I50 values to control. In studies on the site of inhibition of triglyceride synthesis in the overall biosynthetic pathway, serum very low density lipoproteins produced a concentration-dependent inhibition of liver cytosolic phosphatidate phosphohydrolase activity. A higher I50 value was obtained with the hepatic enzyme of the diabetic rats. This higher I50 value was reversed to control by insulin treatment of the diabetic rats. These results indicated that the activity of this enzyme was less sensitive to inhibition by very low density lipoproteins in the ketotic diabetic state. The reduced sensitivity of phosphatidate phosphohydrolase activity to triglyceride inhibition observed in the present studies could explain our previous observation of an increased rate of triglyceride synthesis in ketotic diabetic liver homogenates.
The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone
Authors: Anna-Kaisa Anttonen, Ibrahim Mahjneh, Riikka H Hämäläinen, Clotilde Lagier-Tourenne, Outi Kopra, Laura Waris, Mikko Anttonen, Tarja Joensuu, Hannu Kalimo, Anders Paetau, Lisbeth Tranebjaerg, Denys Chaigne, Michel Koenig, Orvar Eeg-Olofsson, Bjarne Udd, Mirja Somer, Hannu Somer, Anna-Elina Lehesjoki
Journal: Nature Genetics (2005)
Risk of colorectal cancer and other cancers in patients with gall stones.
Authors: C Johansen, W H Chow, T Jorgensen, L Mellemkjaer, G Engholm, J H Olsen
Journal: Gut (1996)

The occurrence of gall stones has repeatedly been associated with an increased risk for cancer of the colon, but risk associated with cholecystectomy remains unclear.To evaluate the hypothesis in a nationwide cohort of more than 40,000 gall stone patients with complete follow up including information of cholecystectomy and obesity.In the population based study described here, 42,098 patients with gall stones in 1977-1989 were identified in the Danish Hospital Discharge Register.These patients were linked to the Danish Cancer Registry to assess their risks for colorectal and other cancers during follow up to the end of 1992.The analysis showed a modest increase in the number of cancers at all sites combined (n = 3940; RR, 1.07; 95% confidence intervals (CI), 1.0 to 1.1). A weak association was found for cancer of the colon (n = 360; RR, 1.09; 95% CI 1.0 to 1.2), which remained unchanged when analysed by sex, anatomical subsite, and duration of follow up. Multivariate analysis with adjustment for cholecystectomy and clinically defined obesity did not change these estimates to any significant extent. Excess risks were found for cancers of the pancreas and the small intestine. A non-significant increased risk for breast cancer was seen in women five years after initial discharge for gall stones.A borderline significant association was seen between gall stones and cancer of the colon, and for cancer of pancreas and small intestine as well as for breast cancer in women.
OCCURRENCE AND PROPERTIES OF A MACROGLOBULIN DIMER IN SOME HYPERGLOBULINEMIC SERA
Authors: T. Suzuki, H. F. Deutsch
Journal: The Journal of Experimental Medicine (1966)

A 22S human gammaM-globulin component has been subjected to various study. It appears to be a dimer of 19S proteins and can undergo reversible molecular transitions which are both pH and temperature dependent. The 22S material regenerated from its 8S subunits no longer undergo similar transformations. Efforts to demonstrate that the 22S material was an antigen-antibody complex of 19S molecules were unsuccessful. Complex precipitin reactions in gels are given by macroglobulins containing this component with antibody to L chains.
Immunospecificity of Nuclear Nonhistone Protein-DNA Complexes in Colon Adenocarcinoma<xref ref-type="fn" rid="FN2">2</xref>
Authors: J F Chiu, W Decha-Umphal, C Markert, B W Little
Journal: JNCI Journal of the National Cancer Institute (1979)

Tumor-specific antisera against dehistonized chromatin isolated from transplantable colon adenocarcinoma (from male noninbred Sprague-Dawley rats) were produced. The specificities of these antisera were determined by complement fixation. In the presence of these antisera, only chromatin from colon adenocarcinoma significantly fixed complement, whereas chromatins isolated from normal rat colon epithelia were inactive. Administration of 1,2-dimethylhydrazine to rats produced an early change in the immunospecificity of colon epithelial chromatin similar to that for colon adenocarcinoma. Several lines of experimental evidence indicated that nuclear antigen was not a carcinoembryonic antigen-like substance. Common antigens were also present in human colon adenocarcinomas.
Purine enzymes in patients with rheumatoid arthritis treated with methotrexate
Authors: A E van Ede
Journal: Annals of the Rheumatic Diseases (2002)

To study (a) purine metabolism during treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine metabolism with efficacy and toxicity of MTX treatment.One hundred and three patients with active RA who started treatment with MTX were included. The initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if necessary. The purine enzymes 5'-nucleotidase (5'NT), purine-nucleoside-phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and adenosine-deaminase (ADA) were measured before the start, after six weeks, and after 48 weeks or at study withdrawal. The laboratory results were related to measures of efficacy and toxicity of MTX treatment.Baseline values of 5'NT and PNP (16.9 and 206.8 nmol/10(6) mononuclear cells/h, respectively) were similar to those in former studies. Activities of HGPRT and ADA were relatively low at the start (8.7 and 80.3 nmol/10(6) mononuclear cells/h, respectively). After six weeks purine enzyme activities showed no important changes from baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of ADA (-21.6 nmol/10(6) mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/10(6) mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/10(6) mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy or toxicity of MTX treatment. In contrast, enzyme activity of 5'NT showed a decrease in the subgroup of patients discontinuing MTX treatment because of hepatotoxicity.MTX treatment in patients with RA leads to a significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that is not related to the anti-inflammatory efficacy or toxicity of MTX. Hepatotoxicity was related to a decrease in the enzyme activity of 5'NT. These changes may be explained by direct or indirect (via purine de novo and salvage metabolism and the homocysteine pathway) effects of MTX.
Clonal Chromosomal Defects in the Molecular Pathogenesis of Refractory Hyperparathyroidism of Uremia
Authors: Yasuo Imanishi, Hideki Tahara, Nallasivam Palanisamy, Sarah Spitalny, Isidro B. Salusky, William Goodman, Maria Luisa Brandi, Tilman B. Drüeke, Emile Sarfati, Pablo Uren[Combining Tilde]a, R. S. K. Chaganti, Andrew Arnold
Journal: Journal of the American Society of Nephrology (2002)

Indirect X chromosome-inactivation analyses have demonstrated that most parathyroid glands from patients with uremic refractory secondary/tertiary hyperparathyroidism are monoclonal neoplasms. However, little is known regarding the specific acquired genetic abnormalities that must underlie such clonal expansion or the molecular pathogenetic features of this disorder, compared with primary parathyroid adenomas. To address these issues in a uniquely powerful manner, both comparative genomic hybridization (CGH) and genome-wide molecular allelotyping were performed with a large group of uremia-associated parathyroid tumors. As indicated by CGH, one or more chromosomal changes were present in 24% of the tumors, which is markedly different from the value for common sporadic adenomas (72%). Two recurrent abnormalities that had not been previously described for sporadic parathyroid adenomas were noted with CGH, i.e., gains on chromosomes 7 (9%) and 12 (11%). Losses on chromosome 11 occurred in only one of the 46 uremia-associated tumors (2%); the tumor also contained a somatic mutation of the remaining MEN1 allele (221del18). A total of 13% of tumors demonstrated recurrent allelic loss on 18q, with 18q21.1-q21.2 being defined as the putative tumor suppressor-containing region. In conclusion, the powerful combination of genome-wide molecular allelotyping and CGH has identified recurrent clonal DNA abnormalities that suggest the existence and locations of genes important in uremic hyperparathyroidism. In addition, genome-wide patterns of somatic DNA alterations, including disparate roles for MEN1 gene inactivation, indicate that markedly different molecular pathogenetic processes exist for clonal outgrowth in severe uremic hyperparathyroidism versus common parathyroid adenomas.
"You don't have to ...": walking to a healthier nation
Authors: Andrew Tannahill
Journal: British Journal of Sports Medicine (2000)

One of the best pieces of public health news in recent years has been that you do not have to be a marathon runner, sports champion, or even regular jogger to derive substantial health benefits through exercise: regular moderate physical activity has cardioprotective and other health benefits.1 From this and our low levels of exercise as a population, it can reasonably be concluded that promoting regular moderate physical activity—active living—is not only the most feasible route for exercise promotion but also the one that will yield the largest population health gain.2

HEBS (the Health Education Board for Scotland) has been something of a pioneer of the active living approach in the United Kingdom.2–4 We place a strong emphasis on walking because of its accessibility. Walking is easy for most people to contemplate and do, regardless of age or fitness level. It does not require special skills, expensive equipment, or facilities. It can be built into everyday life—for example, in commuting, shopping, and leisure. And the risk of injury is generally low.5 HEBS commissioned qualitative research conducted in 1995 supported this notion of accessibility, with preference being shown for walking over swimming …
Collagen-and collagen peptide-induced chemotaxis of human blood monocytes.
Authors: A E Postlethwaite, A H Kang
Journal: The Journal of Experimental Medicine (1976)

The ability of collagen and collagen-derived peptides to act as chemotactic stimuli was investigated by in vitro chemotaxis assays. Native human and chick skin collagen (type I) and alpha-chains obtained from purified chick skin collagen were each chemotactic for human peripheral blood monocytes. In addition, smaller peptides obtained either by digesting native collagen with bacterial collagenase or by degrading purified alpha-chains with cyanogen bromide or pepsin were also chemotactic for monocytes. In contrast, native collagen, alpha-chains, and smaller collagen-derived peptides were not chemotactic for human neutrophils. Since collagen is degraded at sites of tissue damage and inflammation, our findings suggest the possibility that such collagen-derived degradation products might directly serve as chemotactic stimuli for human peripheral blood monocytes in vivo.
Pilot Proteomic Profile of Differentially Regulated Proteins in Right Atrial Appendage Before and After Cardiac Surgery Using Cardioplegia and Cardiopulmonary Bypass
Authors: Richard T. Clements, Gary Smejkal, Neel R. Sodha, Alexander R. Ivanov, John M. Asara, Jun Feng, Alexander Lazarev, Shiva Gautam, Venkatachalam Senthilnathan, Kamal R. Khabbaz, Cesario Bianchi, Frank W. Sellke
Journal: Circulation (2008)

Although highly protective, cardiac surgery using cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to hypothermic reversible ischemic injury that can impair cardiac function which results in a greatly enhanced risk of mortality. Acute changes in myocardial contractile activity are likely regulated via protein modifications. We performed the following study to determine changes in the protein profile of human myocardium following CP/CPB.Right atrial appendage was collected from 8 male patients pre and post-CP/CPB. Atrial tissue lysates were subjected to 2-dimensional electrophoresis, total protein staining, gel averaging, and quantitative densitometry. Ten prominent spots regulated in response to CP/CPB were identified using mass spectrometry. Two hundred twenty-five and 256 protein spots were reliably detected in 2D-gels from pre- and post-CP/CPB patients, respectively. Five unique (ie, not detected post-CP/CPB) and 17 significantly increased spots were detected pre-CP/CPB. Thirty-four unique and 25 significantly increased spots were detected in the post-CP/CPB group. Identified proteins that changed after CP/CPB included: MLC-2a, ATP-synthase delta chain and Enoyl-CoenzymeA hydratase, glutathione-s-transferase omega, alpha-1-acid-glycoprotein, and phosphatidylethanolamine-binding protein.Cardiac surgery results in multiple consistent changes in the human myocardial protein profile. CP/CPB modifies specific cytoskeletal, metabolic, and inflammatory proteins potentially involved in deleterious effects of CP/CPB.
The implicit use of base rates in experiential and ecologically valid tasks
Authors: Barbara A. Spellman
Journal: Behavioral and Brain Sciences (1996)

Abstract When base rates are learned and used in an experiential manner subjects show better base rate use, perhaps because the implicit learning system is engaged. A causal framework in which base rates are relevant might also be necessary. Humans might thus perform better on more ecologically valid tasks, which are likely to contain those three components.