tbuckley/cabot-search huggingface dataset:
FOXM1 Promotes the Warburg Effect and Pancreatic Cancer Progression via Transactivation of LDHA Expression
Authors: Jiujie Cui, Min Shi, Dacheng Xie, Daoyan Wei, Zhiliang Jia, Shaojiang Zheng, Yong Gao, Suyun Huang, Keping Xie
Journal: Clinical Cancer Research (2014)

The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression. However, the regulatory role and underlying mechanisms of FOXM1 in cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by FOXM1 and its impact on pancreatic cancer metabolism.The effect of altered expression of FOXM1 on expression of glycolytic enzymes and tumor development and progression was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer glycolysis were analyzed using in vitro molecular biology. The clinical relevance of aberrant metabolism caused by dysregulated FOXM1 signaling was determined using pancreatic tumor and normal pancreatic tissue specimens.We found that FOXM1 did not markedly change the expression of most glycolytic enzymes except for phosphoglycerate kinase 1 (PGK-1) and lactate dehydrogenase A (LDHA). FOXM1 and LDHA were overexpressed concomitantly in pancreatic tumors and cancer cell lines. Increased expression of FOXM1 upregulated the expression of LDHA at both the mRNA and protein level and elevated LDH activity, lactate production, and glucose utilization, whereas reduced expression of FOXM1 did the opposite. Further studies demonstrated that FOXM1 bound directly to the LDHA promoter region and regulated the expression of the LDHA gene at the transcriptional level. Also, elevated FOXM1-LDHA signaling increased the pancreatic cancer cell growth and metastasis.Dysregulated expression and activation of FOXM1 play important roles in aerobic glycolysis and tumorigenesis in patients with pancreatic cancer via transcriptional regulation of LDHA expression.
Early referral, diagnosis, and treatment of rheumatoid arthritis: evidence for changing medical practice
Authors: S Irvine, R Munro, D Porter
Journal: Annals of the Rheumatic Diseases (1999)

To study the delay in starting disease modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA), and any changes in medical practice between 1980 and 1997.198 consecutive RA patients attending the rheumatology clinics at a teaching hospital, for routine review, had their case sheet reviewed. The dates of symptom onset, general practitioner (GP) referral, first clinic appointment and first use of DMARD were recorded. Data were collected on the erythrocyte sedimentation rate, C reactive protein, rheumatoid factor, and the presence/absence of erosions at the first clinic assessment. Patients were split into four groups according to the date of their first clinic assessment-before 1986, 1987-9, 1990-3, and 1994-7.There was a sharp drop in the delay between symptom onset and GP referral (before 1986, 21 months; 1987-89, 23 months; 1990-3, 7 months; 1994-7, 4 months, p<0.03), and in the delay between first assessment at the rheumatology clinic and the start of DMARD treatment (before 1986, 32 months; 1987-89, 21 months; 1990-1993, 8 months; 1994-7, 1 month, p<0.001). The number of patients given DMARD treatment within six months of symptom onset increased from 5% (before 1994) to 44% (1994-7). Seventy three per cent of patients waiting more than a year from symptom onset to first clinic appointment already had erosive change, compared with 34% of patients seen within a year.Patients are being referred earlier in their disease, and DMARDs are prescribed sooner in the disease course. There has been a substantial increase in the proportion of patients treated with a DMARD within six months of symptom onset.
Carbon monoxide transfer coefficient (transfer factor/alveolar volume) in females<i>versus</i>males: Table 1
Authors: J.M.B. Hughes, N.B. Pride
Journal: European Respiratory Journal (2003)

To the Editors: 

The single breath transfer factor of the lung for carbon monoxide ( T L,CO) is derived from the multiple of the carbon monoxide transfer coefficient ( K CO) and the alveolar volume ( V A) during breath holding 1; consequently, the T L,CO is highly dependent on lung size (∼ V A), and thus is smaller in females for a given height and age. Essentially, the K CO is the rate constant for alveolar carbon monoxide uptake (its units are per second or per minute) and may be expected to be the same in males as in females, as it was in the original description of the technique 2. The published guidelines 3, 4 are not definitive on this point, so we reviewed all studies of reference values for T L,CO and K CO, which have presented data for both males and females.

The European reference values for K CO 3 are derived from the ratio T L,CO predicted/total lung capacity (TLC) predicted. This unusual recommendation arose from correspondence in the ERJ 5, which pointed …
On the Evaluation of Intervention Outcome Risks for Patients With Ischemic Heart Disease
Authors: T. Bruce Ferguson
Journal: Circulation (2008)

of Current English as "a chance or possibility of danger, loss, injury, etc." 1 The evaluation of clinical risk and benefit is a mainstay of all clinical investigation in medicine.More recently, it is slowly becoming a component of everyday clinical care.In this issue of Circulation, Singh et al 2 potentially advance the evaluation of risk in the domain of ischemic heart disease.
Once- and Twice-Daily Dosing With Rosiglitazone Improves Glycemic Control in Patients With Type 2 Diabetes
Authors: Lawrence S. Phillips, George Grunberger, Elizabeth Miller, Rita Patwardhan, Elizabeth B. Rappaport, Alan Salzman
Journal: Diabetes Care (2001)

OBJECTIVE— To determine the efficacy of rosiglitazone compared with placebo in reducing hyperglycemia. RESEARCH DESIGN AND METHODS— After a 4-week placebo run-in period, 959 patients were randomized to placebo or rosiglitazone (total daily dose 4 or 8 mg) for 26 weeks. The primary measure of efficacy was change in the HbAlc concentration. RESULTS— Rosiglitazone produced dosage-dependent reductions in HbAlc of 0.8, 0.9, 1.1, and 1.5% in the 4 mg o.d., 2 mg b.i.d., 8 mg o.d., and 4 mg b.i.d. groups, respectively, compared with placebo. Clinically significant decreases from baseline in HbAlc were observed in drug-naive patients at all rosiglitazone doses and in patients previously treated with oral monotherapy at rosiglitazone 8 mg o.d. and 4 mg b.i.d. Clinically significant decreases from baseline in HbAlc were also observed with rosiglitazone 4 mg b.i.d. in patients previously treated with combination oral therapy. Approximately 33% of drug-naive patients treated with rosiglitazone achieved HbAlc ≤7% at study end. The proportions of patients with at least one adverse event were comparable among the rosiglitazone and placebo groups. There was no evidence of hepatotoxicity in any treatment group. There were statistically significant increases in weight and serum lipids in all rosiglitazone treatment groups compared with placebo. For LDL and HDL cholesterol, the observed increase appeared to be dose related. CONCLUSIONS— Rosiglitazone at total daily doses of 4 and 8 mg significantly improved glycemic control in patients with type 2 diabetes and was well tolerated.
ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models
Authors: Cherrie K. Donawho, Yan Luo, Yanping Luo, Thomas D. Penning, Joy L. Bauch, Jennifer J. Bouska, Velitchka D. Bontcheva-Diaz, Bryan F. Cox, Theodore L. DeWeese, Larry E. Dillehay, Debra C. Ferguson, Nayereh S. Ghoreishi-Haack, David R. Grimm, Ran Guan, Edward K. Han, Rhonda R. Holley-Shanks, Boris Hristov, Kenneth B. Idler, Ken Jarvis, Eric F. Johnson, Lawrence R. Kleinberg, Vered Klinghofer, Loren M. Lasko, Xuesong Liu, Kennan C. Marsh, Thomas P. McGonigal, Jonathan A. Meulbroek, Amanda M. Olson, Joann P. Palma, Luis E. Rodriguez, Yan Shi, Jason A. Stavropoulos, Alan C. Tsurutani, Gui-Dong Zhu, Saul H. Rosenberg, Vincent L. Giranda, David J. Frost
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with Kis of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d × 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
THE RELATION BETWEEN BLOOD DESTRUCTION AND THE OUTPUT OF BILE PIGMENT
Authors: G. O. Broun, Philip D. McMaster, Peyton Rous
Journal: The Journal of Experimental Medicine (1923)

In dogs intubated for the collection of all of the bile, a marked falling off in the yield of bilirubin is regularly to be noted after operation, followed soon by an anemia of secondary character. Though, in the absence of complications, the anemia is mild, it persists despite the excellent general condition of the animal. Intercurrent changes in the hemoglobin percentage take place from time to time, and these are accompanied by very similar fluctuations in the bilirubin quantity. At first inspection the data strongly suggest that blood destruction finds accurate quantitative expression in the yield of bile pigment. But this is not the case. True, the destruction finds expression in terms of bile pigment and practically at once; and the data support the conception that bilirubin has no other sources besides the hemoglobin of destroyed blood. But our experiments show that the amount of it put forth during the development of an anemia from gradual blood destruction, either intercurrent or induced, is far below that derivable from the net quantity of hemoglobin disappearing from the circulation. The discrepancy is referable to a process of pigment conservation which varies in proportion to the body need. We have shown in a previous paper that bile pigment may on occasion beabsorbed from the intestinal tract. This fact and those reported in the present communication lead one to question the accepted view that bilirubin is mere waste material eliminated by way of the liver. The anemia which develops upon total loss of the bile is not improbably consequent on the pigment loss therewith. Current methods of computing the rate of normal and pathological blood destruction from the bilirubin (or urobilin) yield are unsound in principle and open to large error in practise. Yet there is no doubt that day-to-day variations in the output of bile pigment result from changes in the blood; and on occasion they provide enlightening evidence of the nature of hemic events.
RELIABILITY OF PSYCHIATRIC DIAGNOSES: 2. A STUDY OF CONSISTENCY OF CLINICAL JUDGMENTS AND RATINGS
Authors: A. T. BECK, C. H. WARD, M. MENDELSON, J. E. MOCK, J. K. ERBAUGH
Journal: American Journal of Psychiatry (1962)

1. An investigation of the reliability of psychiatric diagnoses was designed to minimize factors that would artificially lower or inflate the rate of concordance. A series of 153 patients were examined independently by paired psychiatrists and diagnoses were made independently according to the standard nomenclature. The degree of agreement (54%) on specific diagnoses was statistically significant (p<.001) and was higher than that obtained in other comparable studies. 2. In cases where both diagnosticians indicated they were certain of the diagnosis, the agreement rate (81%) was found to be significantly higher than in the remaining cases. 3. When the diagnosticians gave both a preferred diagnosis and an alternative diagnosis, it was found that the rate of agreement between either diagnosis offered by one diagnostician and either diagnosis of the other was 82%. This suggested that the diagnosticians may have been closer in their appraisals than indicated by the scoring of only the preferred diagnoses. 4. An additional method of classification consisted of rating the patients on a 4-point scale along a single dimension, viz., the depth of depression. It was found that, when they used this method, the diagnosticians agreed within one scale unit in 99% of the cases. 5. It was suggested that the present system of diagnosis could be improved by focusing greater attention on appropriate training in diagnostic skills, the identification of the defects in current interviewing techniques, and the development of more uniform clinical procedures.
Reduced Sox9 Function Promotes Heart Valve Calcification Phenotypes In Vivo
Authors: Jacqueline D. Peacock, Agata K. Levay, Devin B. Gillaspie, Ge Tao, Joy Lincoln
Journal: Circulation Research (2010)

Calcification of heart valve structures is the most common form of valvular disease and is characterized by the appearance of bone-like phenotypes within affected structures. Despite the clinical significance, the underlying etiology of disease onset and progression is largely unknown and valve replacement remains the most effective treatment. The SRY-related transcription factor Sox9 is expressed in developing and mature heart valves, and its function is required for expression of cartilage-associated proteins, similar to its role in chondrogenesis. In addition to cartilage-associated defects, mice with reduced sox9 function develop skeletal bone prematurely; however, the ability of sox9 deficiency to promote ectopic osteogenic phenotypes in heart valves has not been examined.This study aims to determine the role of Sox9 in maintaining connective tissue homeostasis in mature heart valves using in vivo and in vitro approaches.Using histological and molecular analyses, we report that, from 3 months of age, Sox9(fl/+);Col2a1-cre mice develop calcific lesions in heart valve leaflets associated with increased expression of bone-related genes and activation of inflammation and matrix remodeling processes. Consistently, ectopic calcification is also observed following direct knockdown of Sox9 in heart valves in vitro. Furthermore, we show that retinoic acid treatment in mature heart valves is sufficient to promote calcific processes in vitro, which can be attenuated by Sox9 overexpression.This study provides insight into the molecular mechanisms of heart valve calcification and identifies reduced Sox9 function as a potential genetic basis for calcific valvular disease.
Adaptive Evolution of Signaling Partners
Authors: Daisuke Urano, Taoran Dong, Jeffrey L. Bennetzen, Alan M. Jones
Journal: Molecular Biology and Evolution (2015)

Proteins that interact coevolve their structures. When mutation disrupts the interaction, compensation by the partner occurs to restore interaction otherwise counterselection occurs. We show in this study how a destabilizing mutation in one protein is compensated by a stabilizing mutation in its protein partner and their coevolving path. The pathway in this case and likely a general principle of coevolution is that the compensatory change must tolerate both the original and derived structures with equivalence in function and activity. Evolution of the structure of signaling elements in a network is constrained by specific protein pair interactions, by requisite conformational changes, and by catalytic activity. The heterotrimeric G protein-coupled signaling is a paragon of this protein interaction/function complexity and our deep understanding of this pathway in diverse organisms lends itself to evolutionary study. Regulators of G protein Signaling (RGS) proteins accelerate the intrinsic GTP hydrolysis rate of the Gα subunit of the heterotrimeric G protein complex. An important RGS-contact site is a hydroxyl-bearing residue on the switch I region of Gα subunits in animals and most plants, such as Arabidopsis. The exception is the grasses (e.g., rice, maize, sugarcane, millets); these plants have Gα subunits that replaced the critical hydroxyl-bearing threonine with a destabilizing asparagine shown to disrupt interaction between Arabidopsis RGS protein (AtRGS1) and the grass Gα subunit. With one known exception (Setaria italica), grasses do not encode RGS genes. One parsimonious deduction is that the RGS gene was lost in the ancestor to the grasses and then recently acquired horizontally in the lineage S. italica from a nongrass monocot. Like all investigated grasses, S. italica has the Gα subunit with the destabilizing asparagine residue in the protein interface but, unlike other known grass genomes, still encodes an expressed RGS gene, SiRGS1. SiRGS1 accelerates GTP hydrolysis at similar concentration of both Gα subunits containing either the stabilizing (AtGPA1) or destabilizing (RGA1) interface residue. SiRGS1 does not use the hydroxyl-bearing residue on Gα to promote GAP activity and has a larger Gα-interface pocket fitting to the destabilizing Gα. These findings indicate that SiRGS1 adapted to a deleterious mutation on Gα using existing polymorphism in the RGS protein population.
Treatment of Vitamin D Insufficiency in Postmenopausal Women
Authors: Karen E. Hansen, R. Erin Johnson, Kaitlin R. Chambers, Michael G. Johnson, Christina C. Lemon, Tien Nguyen Thuy Vo, Sheeva Marvdashti
Journal: JAMA Internal Medicine (2015)

<h3>Importance</h3> Experts debate optimal 25-hydroxyvitamin D (25[OH]D) levels for musculoskeletal health. <h3>Objective</h3> To compare the effects of placebo, low-dose cholecalciferol, and high-dose cholecalciferol on 1-year changes in total fractional calcium absorption, bone mineral density, Timed Up and Go and five sit-to-stand tests, and muscle mass in postmenopausal women with vitamin D insufficiency. <h3>Design, Setting, and Participants</h3> This randomized, double-blind, placebo-controlled clinical trial was conducted at a single center in Madison, Wisconsin, from May 1, 2010, through July 31, 2013, and the final visit was completed on August 8, 2014. A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied. <h3>Interventions</h3> Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D<sub>3</sub>and twice monthly yellow placebo (n=75), and daily white placebo and twice monthly 50,000 IU vitamin D<sub>3 </sub>(n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels ≥30 ng/mL. <h3>Main Outcomes and Measures</h3> Outcome measures were 1-year change in total fractional calcium absorption using 2 stable isotopes, bone mineral density and muscle mass using dual energy x-ray absorptiometry, Timed Up and Go and five sit-to-stand tests, functional status (Health Assessment Questionnaire), and physical activity (Physical Activity Scale for the Elderly), with Benjamini-Hochberg correction of<i>P</i>values to control for the false discovery rate. <h3>Results</h3> After baseline absorption was controlled for, calcium absorption increased 1% (10 mg/d) in the high-dose arm but decreased 2% in the low-dose arm (<i>P</i> = .005 vs high-dose arm) and 1.3% in the placebo arm (<i>P</i> = .03 vs high-dose arm). We found no between-arm changes in spine, mean total-hip, mean femoral neck, or total-body bone mineral density, trabecular bone score, muscle mass, and Timed Up and Go or five sit-to-stand test scores. Likewise, we found no between-arm differences for numbers of falls, number of fallers, physical activity, or functional status. <h3>Conclusions and Relevance</h3> High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts' recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00933244
Comparative observations on inorganic and organic lead neurotoxicity.
Authors: M A Verity
Journal: Environmental Health Perspectives (1990)

Environmental and occupational exposure to lead still generates concern, and recent studies have focused such concern on the role of body burden of lead during the fetal/neonatal period, especially in the genesis of disturbed central nervous system development. This discussion provides some comparative observations on the neurotoxicity of inorganic and organic lead species. The characteristics acute, predominantly cerebellar encephalopathy associated with neonatal high lead exposure contrasts to the subtle, axo-dendritic disorganization shown to be associated with low-level neonatal inorganic Pb2+ exposure. There is a preferential involvement of the hippocampus in both low-level inorganic Pb2+ and organolead exposure, and the clinical syndromes of irritability, hyperactivity, aggression, and seizures are common features of disturbed hippocampal function. Neurotransmitter system abnormalities have been described with inorganic Pb2+, but recent attention has focused on the abnormalities in glutamate, dopamine and/or gamma-aminobutyric acid (GABA) uptake, efflux, and metabolism. Abnormalities of GABA and glutamate metabolism are also found with the organolead species. While the pathogenesis is still unclear, the interactive role of Pb2+ on mitochondrial energy metabolism, Ca2+ uptake, intracellular Ca2+ homeostasis, and neurotransmitter influx/efflux is considered. Consideration is given to low-dose inorganic Pb2+ and organolead effects on mitochondrial and/or plasmalemmal membranes inducing either Cl-/OH- antiport-linked depolarization, inhibition of intracellular ATP biosynthesis and transduction. and/or abnormalities induced due to the preferential affinity of Pb2+ for intracellular Ca2(+)-cytoplasmic protein, e.g. calmodulin. Testable hypotheses are presented that may provide an understanding of the pathogenesis underlying dystrophic neuronal development under the influence of inorganic or organolead intoxication.