tbuckley/cabot-search huggingface dataset:
Abstract 2938: Altered caspase-8 protein expression and activity in TRAIL-resistant normal human fibroblasts.
Authors: Roslyn N. Crowder, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2013)

Abstract TNF-related apoptosis-inducing ligand (TRAIL)-mediated cell death is currently being utilized in newly developed cancer therapies. The molecular basis of normal cell resistance to TRAIL-mediated apoptosis, and thus therapeutic index, remains largely unexplored. We investigated TRAIL sensitivity in normal fibroblasts (HFF, WI-38, MRC-5) and found that normal fibroblasts have decreased protein expression of initiator caspase-8 that is required for complete TRAIL signaling. TRAIL treatment caused caspase-8 cleavage in TRAIL-sensitive cancer cells. Yet, no caspase-8 cleavage was observed in normal fibroblasts after TRAIL treatment. TRAIL treated fibroblasts had modest increase in caspase-8 activity compared to TRAIL-susceptible cancer cells. Previous studies have found caspase-8 polyubiquitination necessary for caspase-8 aggregation and complete activation. Additionally, reports show deubiquitination of caspase-8 limits caspase-8 activity. Therefore, we examined caspase-8 ubiquitination in normal fibroblasts. Caspase-8 ubiquitination, analyzed by Western blotting, in normal fibroblasts was found to be decreased compared to TRAIL-sensitive cancer cells. TRAIL sensitivity in normal fibroblasts after treatment with deubiquitinase inhibitor PR-619 was also assessed. Normal fibroblasts had markedly decreased cell viability after co-treatment with TRAIL and PR-619 compared to TRAIL-only treated fibroblasts. Cancer cell viability after co-treatment with TRAIL and PR-619 was similar to cancer cells merely treated with TRAIL. Normal fibroblasts co-treated with TRAIL and PR-619 had increased caspase-8 cleavage, PARP cleavage, and caspase-8 activity. The increased cell death seen in normal fibroblasts with TRAIL and PR-619 co-treatment was greatly inhibited when caspase inhibitor ZVAD was added, demonstrating the cell death with TRAIL and PR-619 was caspase-mediated. Our data suggest that caspase-8 deubiquitination may be a contributing factor in normal fibroblast resistance to TRAIL-mediated apoptosis. Our current studies are focused on investigating the role of deubiquitinase A20, previously found to deubiquitinate caspase-8, in normal fibroblast caspase-8 deubiquitination. Citation Format: Roslyn N. Crowder, David T. Dicker, Wafik S. El-Deiry. Altered caspase-8 protein expression and activity in TRAIL-resistant normal human fibroblasts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2938. doi:10.1158/1538-7445.AM2013-2938
Dyspepsia: An Investigation
Authors: H. Edwards, W. S. C. Copeman
Journal: BMJ (1943)

SURNALHomission of these 17 cases from the appropriate categories makes no difference to the general trend of the results.Setum reactions were noted in only 3 of the 114 patients in the series treated with antitoxin ; these occurred after some hours or days in the form of a rash or pyrexia, and apparently gave no cause for anxiety.
Mineral and Vitamin Status on High-Fiber Diets: Long-Term Studies of Diabetic Patients
Authors: James W Anderson, Susan K Ferguson, Dennis Karounos, Linda O'Malley, Beverly Sieling, Wen-Ju J Chen
Journal: Diabetes Care (1980)

High-fiber diets have a beneficial impact on glucose metabolism of selected persons with diabetes mellitus. A major concern is the long-term effects of fiber intake on mineral and vitamin status. We measured serum concentrations of selected minerals and vitamins and also assessed three fat-soluble vitamins in 15 patients fed high-fiber diets for an average of 21 mo. Average values for serum calcium, phosphorus, alkaline phosphatase, iron-binding capacity, magnesium, and hemoglobin values were normal. Vitamin B12 and folic acid concentrations in serum were also normal. Indirect assessment suggested that these patients had adequate intakes of the fat-soluble vitamins A, D, and K. These preliminary observations suggest that high-fiber diets containing a wide variety of natural foods are well tolerated for up to 51 mo; we failed to detect evidence suggesting mineral or vitamin deficiency in these patients.
Proceedings: Radiological changes in the age group 5 to 24 years of the population of Azmoos, Switzerland.
Authors: B Ansell, J Sidler, W M Zinn
Journal: Annals of the Rheumatic Diseases (1975)

Heberden Society 199 biopsy was normal in 35 % of investigations, while reactive hepatitis was seen in 43 % and fatty liver in 22 %.Reactive hepatitis was mild in 6 %, moderate in 15 %, and severe in 22% of biopsies; fatty liver was mild in 11 %, moderate in 7 %, and severe in 4% of specimens.An abnormal BSP test was observed in 75 % of investigations, raised alkaline phosphatase in about 50%, an abnormal thymol turbidity test in 24 %, and diminished prothrombin (Quick) in 20%.A rise in transaminases in serum and in urobilinogen in urine was, however, very rare.A rise in bilirubin (more than 1-0 mgll00 ml) was never observed.There was a close relationship between rheumatoid arthritis activity and abnormal BSP retention, raised alkaline phosphatase, and reactive hepatitis.These tests, however, were not correlated to duration or stage of arthritis nor age of patients.These data were obtained in West Germany.In a second series in Switzerland, liver function tests, as well as liver biopsies, were carried out in 51 patients with definite rheumatoid arthritis.BSP retention was abnormal and prothrombin in 60 % of cases, alkaline phosphatase in 20%, thymol turbidity test in all 25 patients examined.Slightly raised levels of transaminases were seen in about
Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2
Authors: Irina V. Grigorieva, Samantha Mirczuk, Katherine U. Gaynor, M. Andrew Nesbit, Elena F. Grigorieva, Qiaozhi Wei, Asif Ali, Rebecca J. Fairclough, Joanna M. Stacey, Michael J. Stechman, Radu Mihai, Dorota Kurek, William D. Fraser, Tertius Hough, Brian G. Condie, Nancy Manley, Frank Grosveld, Rajesh V. Thakker
Journal: Journal of Clinical Investigation (2010)

Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role of GATA3 in parathyroid function by challenging Gata3+/- mice with a diet low in calcium and vitamin D so as to expose any defects in parathyroid function. This led to a higher mortality among Gata3+/- mice compared with Gata3+/+ mice. Compared with their wild-type littermates, Gata3+/- mice had lower plasma concentrations of calcium and parathyroid hormone (PTH) and smaller parathyroid glands with a reduced Ki-67 proliferation rate. At E11.5, Gata3+/- embryos had smaller parathyroid-thymus primordia with fewer cells expressing the parathyroid-specific gene glial cells missing 2 (Gcm2), the homolog of human GCMB. In contrast, E11.5 Gata3-/- embryos had no Gcm2 expression and by E12.5 had gross defects in the third and fourth pharyngeal pouches, including absent parathyroid-thymus primordia. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays showed that GATA3 binds specifically to a functional double-GATA motif within the GCMB promoter. Thus, GATA3 is critical for the differentiation and survival of parathyroid progenitor cells and, with GCM2/B, forms part of a transcriptional cascade in parathyroid development and function.
Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited
Authors: Gustav Paumgartner, Ulrich Beuers
Journal: Hepatology (2002)

Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, resulting from modulation of the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocytes; (2) stimulation of hepatobiliary secretion, putatively via Ca 2+ - and protein kinase C-α-dependent mechanisms and/or activation of p38 MAPK and extracellular signal-regulated kinases (Erk) resulting in insertion of transporter molecules ( e.g. , bile salt export pump, BSEP, and conjugate export pump, MRP2) into the canalicular membrane of the hepatocyte and, possibly, activation of inserted carriers; (3) protection of hepatocytes against bile acid-induced apoptosis, involving inhibition of mitochondrial membrane permeability transition (MMPT), and possibly, stimulation of a survival pathway. In primary biliary cirrhosis, UDCA (13-15 mg/kg/d) improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival. In primary sclerosing cholangitis, UDCA (13-20 mg/kg/d) improves serum liver chemistries and surrogate markers of prognosis, but effects on disease progression must be further evaluated. Anticholestatic effects of UDCA have also been reported in intrahepatic cholestasis of pregnancy, liver disease of cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host disease. Future efforts will focus on definition of additional clinical uses of UDCA, on optimized dosage regimens, as well as on further elucidation of mechanisms of action of UDCA at the molecular level.
THE LIBERATION OF RENIN BY PERFUSION OF KIDNEYS FOLLOWING REDUCTION OF PULSE PRESSURE
Authors: K. G. Kohlstaedt, Irvine H. Page
Journal: The Journal of Experimental Medicine (1940)

1. Isolated dogs' kidneys have been perfused with defibrinated blood under hemodynamic conditions similar to those in the body. Under these circumstances blood flow, urine secretion, and oxygen consumption are well maintained, but urea clearance is low. Renal venous blood collected initially and at the end of 3 or more hours of perfusion exhibited no difference in vasoconstriction properties when perfused along with renin or renin-activator through an isolated rabbit's ear. 2. Reduction of pulse pressure by constricting the renal artery may be performed without reducing mean pressure significantly. Impairment of urea clearance and rate of urine secretion follow, and oxygen consumption is slightly reduced. 3. After an hour or more of perfusion with reduced pulse pressure, gradual rise in mean renal arterial pressure distal to the clamp and reduction of blood flow occur. 4. Renal venous blood collected after about one hour of perfusion with reduced pulse pressure differs from that collected before reduction of pulse pressure in that it causes intense vasoconstriction when perfused with renin-activator through an isolated rabbit's ear. 5. Perfusion of a dog's hind leg under similar circumstances does not cause this change in the venous blood to occur.
POLIOMYELITIS IN THE CYNOMOLGUS MONKEY
Authors: Harold K. Faber, Rosalie J. Silverberg, Luther Dong
Journal: The Journal of Experimental Medicine (1943)

1. Repeated non-traumatic exposures to poliomyelitis virus of the mucous membranes of the upper respiratory tract and of various portions of the alimentary tract in 5 cynomolgus monkeys, extending over a period of 9 to 14 months, were followed by a definite, though limited resistance to intracerebral inoculation to the homologous strain of virus in 4 of them. Only one monkey developed paralysis (20 per cent incidence) and the other 4 remained free of signs and symptoms of the disease. 92 per cent of 25 previously untreated monkeys developed paralysis with the same strain after intracerebral inoculation. 2. Microscopic examination of the central and peripheral nervous systems of the 4 non-paralytic cases revealed in all instances typical lesions in the central nervous system descending from the level of inoculation into the brain-stem but in only 2 into the spinal cord and then only in limited, small areas. Lesions were found in the peripheral ganglia in all animals which corresponded in distribution with the surface membranes previously exposed to virus. No lesions were found in the central nervous system indicative of invasion preceding the intracerebral inoculation. 3. Our observations point to the acquisition by the immune animal, as a result of surface exposure, of the power to limit the spread of infection in the central nervous system rather than of the capacity entirely to prevent implantation and multiplication of virus. 4. This limitation of spread, it is suggested, resembles the tendency so commonly seen in human poliomyelitis of the disease to "halt" at some stage of its evolution, resulting in the various clinical gradations in extent and severity of involvement (subclinical, abortive, non-paralytic, mild paralytic forms, etc.) 5. The experimental methods of exposure, previous to intracerebral inoculation, employed in our study are compared with the natural exposures of human beings during the course of life, which, as age advances, lead to increasing resistance to poliomyelitis and to an increasing incidence of specific neutralizing antibodies in the blood. 6. The mechanism of resistance is obscure. It may be related to the continuing presence of infection in the peripheral ganglia but this is as yet unproved.
Comparison of Biostimulation versus Bioaugmentation with Bacterial Strain PM1 for Treatment of Groundwater Contaminated with Methyl <i>Tertiary</i> Butyl Ether (MTBE)
Authors: Amanda E. Smith, Krassimira Hristova, Isaac Wood, Doug M. Mackay, Ernie Lory, Dale Lorenzana, Kate M. Scow
Journal: Environmental Health Perspectives (2004)

Widespread contamination of groundwater by methyl tertiary butyl ether (MTBE) has triggered the exploration of different technologies for in situ removal of the pollutant, including biostimulation of naturally occurring microbial communities or bioaugmentation with specific microbial strains known to biodegrade the oxygenate. After laboratory studies revealed that bacterial strain PM1 rapidly and completely biodegraded MTBE in groundwater sediments, the organism was tested in an in situ field study at Port Hueneme Naval Construction Battalion Center in Oxnard, California. Two pilot test plots (A and B) in groundwater located down-gradient from an MTBE source were intermittently sparged with pure oxygen. Plot B was also inoculated with strain PM1. MTBE concentrations up-gradient from plots A and B initially varied temporally from 1.5 to 6 mg MTBE/L. Six months after treatment began, MTBE concentrations in monitoring wells down-gradient from the injection bed decreased substantially in the shallow zone of the groundwater in plots A and B, thus even in the absence of the inoculated strain PM1. In the deeper zone, downstream MTBE concentrations also decreased in plot A and to a lesser extent in plot B. Difficulties in delivery of oxygen to the deeper zone of plot B, evidenced by low dissolved oxygen concentrations, were likely responsible for low rates of MTBE removal at that location. We measured the survival and movement of strain PM1 in groundwater samples using two methods for detection of DNA sequences specific to strain PM1: TaqMan quantitative polymerase chain reaction, and internal transcribed spacer region analysis. A naturally occurring bacterial strain with > 99% 16S rDNA sequence similarity to strain PM1 was detected in groundwater collected at various locations at Port Hueneme, including outside the plots where the organism was inoculated. Addition of oxygen to naturally occurring microbial populations was sufficient to stimulate MTBE removal at this site. In some cases, however, inoculation with an MTBE-degrading culture may be warranted.
Uncertainty over Redditch hospital's emergency department led to mass resignation, say campaigners
Authors: M. Limb
Journal: BMJ (2015)

An NHS trust will advertise this week to replace a team of emergency consultants who resigned en masse amid continuing uncertainty over a review of acute services.

Worcestershire Acute Hospitals NHS Trust said that emergency services would continue “as normal” after five consultants handed in their resignations—four from the Alexandra Hospital in Redditch and one from Worcestershire Royal Hospital.

Campaigners said that delays to a review of acute services had left accident and emergency (A&E) consultants “in limbo” over their future, amid fears that the Alexandra Hospital would lose its A&E department. The consultants have all been offered jobs at Warwick Hospital.

Worcestershire Acute Hospitals NHS Trust said that it recognised the risk that staff could leave …
Mastalgia: psychoneurosis or organic disease?
Authors: P E Preece, R E Mansel, L E Hughes
Journal: BMJ (1978)

To test the traditional surgical view that pain in the breast is largely an expression of psychoneurosis, the Middelesex Hospital Questionnaire was given to 317 women with mastalgia and 170 controls with varicose veins. Their scores were compared with those of 173 women psychiatric outpatients tested by the designers of the questionnaire. The results were broadly similar in the mastalgia and varicose veins groups, and where there were significant differences women with varicose veins had a higher psychoneurotic score in each case. Within the mastalgia group no difference in scores was observed between patients with cyclical mastalgia and those with mastalgia due to periductal mastitis. Both groups of surgical outpatients had significantly lower scores in major traits than the psychiatric group, except for a small group of patients with breast pain who persistently failed to respond to treatment. Patients with mastalgia are therefore no more "neurotic" than those with varicose veins, and differ greatly from patients with recognized psychoneurosis. Most patients have a physiological or pathological basis for their breast pain, and they deserve an appropriate diagnostic and therapeutic approach.
Nanoparticles Deliver Triplex-forming PNAs for Site-specific Genomic Recombination in CD34+ Human Hematopoietic Progenitors
Authors: Nicole A McNeer, Joanna Y Chin, Erica B Schleifman, Rachel J Fields, Peter M Glazer, W Mark Saltzman
Journal: Molecular Therapy (2010)

Triplex-forming peptide nucleic acids (PNAs) are powerful gene therapy agents that can enhance recombination of short donor DNAs with genomic DNA, leading to targeted and specific correction of disease-causing genetic mutations. Therapeutic use of PNAs is severely limited, however, by challenges in intracellular delivery, particularly in clinically relevant targets such as hematopoietic stem and progenitor cells. Here, we demonstrate efficient and nontoxic PNA-mediated recombination in human CD34(+) cells using poly(lactic-co-glycolic acid) (PLGA) nanoparticles for intracellular oligonucleotide delivery. Treatment of progenitor cells with nanoparticles loaded with PNAs and DNAs targeting the β-globin locus led to levels of site-specific modification in the range of 0.5-1% in a single treatment, without detectable loss in cell viability, resulting in a 60-fold increase in modified and viable cells as compared to nucleofection. As well, the differentiation capacity of the progenitor cells treated with nanoparticles did not change relative to untreated progenitor cells, indicating that nanoparticles are safe and minimally disruptive delivery vectors for PNAs and DNAs to mediate gene modification in human primary cells. This is the first demonstration of the use of biodegradable nanoparticles to deliver genome-editing agents to human primary cells, and provides a strong rationale for systemic delivery of complex nucleic acid mixtures designed for gene correction.
Minister's discouraging response to perinatal report
Authors: W. Russell
Journal: BMJ (1980)

The response by Mr Patrick Jenkin, Social Services Secretary, to the report on perinatal and neonatal mortality from the Social Services Committee was, to say the least, discouraging.Though the tenor of his reply (Cmnd 8084, HMSO, C4-60) was hardly unexpected in these cash-conscious days, it certainly depressed the committee's chairman, Mrs Renee Short, Labour MP for Wolverhampton North East.In particular, the absence of any hint that additional resources could be provided for the perinatal and neonatal services upset her.She told me she regarded that as "very serious indeed."She also latched on to the rather fulsome introduction to the reply in which Mr Jenkin said the report's scope and wealth of material would ensure it a place in a long and distinguished succession of reports starting with the report of the Cranbrook Committee in 1959."Nothing was done about them," she remarked acidly."Is he putting us on the shelf to gather dust as well ?"The answer to that is not if she and her colleagues on the all-party committee can help it.They will be using every parliamentary opportunity, something denied the authors of the previous reports, to keep their recommendations alive.Mrs Short also blamed the tone of the reply on attitudes at the Department of Health and Social Security."It is quite clear they are not prepared to give the reduction of perinatal mortality- that is, saving babies' lives-the priority it needs," she said."I think they allowed their own prejudices to colour their attitude to our report."She reckons that the Department's priorities remain what are known as the Cinderella services-the elderly, mental health, and the disabled.The point was made by Mr Jenkin, who said the dilemma was whether, in order to accelerate the continuing fall in perinatal mortality, it would be right to impose on health authorities a substantial diversion of funds at the expense of other groups.Mrs Short was also scathing about his claim that the committee's estimates of the cost of their proposals was unrealistic.He should go back and redo his sums.Mr Jenkin's reply challenges the accuracy of the committee's most dramatic finding-that there are 5000 avoidable deaths and 5000 preventable cases of handicap among babies each year.