tbuckley/cabot-search huggingface dataset:
Proteolytic Activation of Protein Kinase C δ by an ICE/CED 3-like Protease Induces Characteristics of Apoptosis
Authors: Tariq Ghayur, Margaret Hugunin, Robert V. Talanian, Sheldon Ratnofsky, Christopher Quinlan, Yutaka Emoto, Pramod Pandey, Rakesh Datta, Yinyin Huang, Surender Kharbanda, Hamish Allen, Robert Kamen, Winnie Wong, Donald Kufe
Journal: The Journal of Experimental Medicine (1996)

Recent studies have shown that protein kinase C (PKC) δ is proteolytically activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. However, the relationship of PKCδ cleavage to induction of apoptosis is unknown. The present studies demonstrate that full-length PKCδ is cleaved at DMQD330N to a catalytically active fragment by the cysteine protease CPP32. The results also demonstrate that overexpression of the catalytic kinase fragment in cells is associated with chromatin condensation, nuclear fragmentation, induction of sub-G1 phase DNA and lethality. By contrast, overexpression of full-length PKCδ or a kinase inactive PKCδ fragment had no detectable effect. The findings suggest that proteolytic activation of PKCδ by a CPP32-like protease contributes to phenotypic changes associated with apoptosis.
The Importance of Obesity in the Development of Coronary Risk Factors and Disease: The Epidemiologic Evidence
Authors: H B Hubert
Journal: Annual Review of Public Health (1986)

Coronary heart disease (CHD) is caused by a complex interaction of genetic and life-style factors that begin to exert their effects many years prior to diagnosis of the disease. Numerous epidemiologic studies in middle-aged populations have shown the importance of attributes such as elevated blood pressure and blood lipids in the etiology of CHD; as a result, intervention in high-risk individuals has been focused on reduction of risk factors with pharmacologic treatment and a modified-fat diet. While such approaches to risk reduction are important and can decrease mortality, it is also clear that optimal preventive strategies will require modification of early markers for the development of CHD, hyperten­ sion, and hyperlipidemia. The accumulated evidence strongly suggests that overweight or obesity is such a precursor to disease development and that prevention of CHD can be greatly promoted by the control of this attribute in overfed and sedentary populations such as those in North America.
Functionally Novel Tumor Necrosis Factor-α–Modulated CHR-Binding Protein Mediates Cyclin A Transcriptional Repression in Vascular Endothelial Cells
Authors: Raj Kishore, Ioakim Spyridopoulos, Corinne Luedemann, Douglas W. Losordo
Journal: Circulation Research (2002)

Local expression of tumor necrosis factor-α (TNF-α) at the sites of arterial injury after balloon angioplasty, suppresses endothelial cell (EC) proliferation and negatively affects reendothelialization of the injured vessel. We have previously reported that in vitro exposure of ECs to TNF-α induced EC growth arrest and apoptosis. These effects were mediated, at least in part, by downregulation of cell cycle regulatory proteins. In the present study, we report potential mechanism(s) for TNF-α–mediated suppression of cyclin A in ECs. TNF-α exposure to ECs completely abrogated cyclin A mRNA expression via mechanisms involving both transcriptional and posttranscriptional modifications. TNF-α inhibited de novo cyclin A mRNA synthesis and suppressed cyclin A promoter activity. Utilizing deletion mutants of human cyclin A promoter, we have identified CDE-CHR ( C ell cycle– D ependent E lements– C ell cycle genes H omology R egion) region of cyclin A promoter as a target for TNF-α suppressive action. Experiments to investigate CDE-CHR binding proteins/factors revealed a TNF-α–mediated increase in specific DNA binding activity to the CHR elements. This increase in binding activity by TNF-α was mediated via the induction of a functionally novel 84-kDa protein that binds specifically to CHR in Southwestern assays. UV cross-linking and SDS-PAGE analysis of proteins eluted from specific complex confirmed the presence of this 84-kDa protein. Moreover, induction of this protein by TNF-α was protein synthesis dependent. Additionally, exposure of ECs to TNF-α markedly reduced cyclin A mRNA stability. Targeted disruption of this protein could potentially be a therapeutic strategy to rescue EC proliferation in vivo.
Pattern and prognosis of liver function test abnormalities during parenteral nutrition in inflammatory bowel disease
Authors: Jose M. Bengoa, Stephen B. Hanauer, Michael D. Sitrin, Alfred L. Baker, Irwin H. Rosenberg
Journal: Hepatology (1985)

The pattern of liver function test abnormalities was examined during total parenteral nutrition (TPN), using both dextrose and fat emulsions as caloric sources, in 92 patients with inflammatory bowel disease. Seventy–two patients had completely normal tests before TPN while 20 had one or more abnormal liver function tests before TPN was started. Serum bilirubin levels were normal in all patients before TPN; within 2 weeks on TPN, 25% of patients had elevated bilirubin levels. Serum alkaline phosphatase rose to values above normal in 25% of patients with normal starting values but did not change in those with abnormal baseline liver function tests. Elevations of SGPT were characteristically more pronounced than were elevation of SGOT. After 2 weeks of TPN, mean serum SGOT rose from 15 to 26 IU per liter (p &lt; 0.01) in patients with normal baseline values and from 28 to 50 IU per liter in those with abnormal baseline values. Elevations of serum SGPT were most common, affecting 25% of patients with normal baseline. The mean SGPT value rose from 13 to 38 IU per liter (p &lt; 0.01) at 1 week of TPN. In patients with abnormal tests before TPN, the mean SGPT value rose from 45 to 102 IU per liter (p &lt; 0.05). Liver biopsies performed in four patients with substantial elevations of aminotransferases revealed only minor nonspecific changes and no fatty infiltration. Elevated liver function tests promptly returned to baseline after TPN was discontinued, and progressive liver disease was not observed in any patient. Although abnormalities of liver function tests, particularly the aminotransferases, are common during balanced TPN in patients with inflammatory bowel disease, the favorable prognosis and benign histologic changes argue against the need to discontinue TPN in the presence of such changes.
Steroid-induced myopathy and its significance to respiratory disease: a known disease rediscovered
Authors: PN Dekhuijzen, M Decramer
Journal: European Respiratory Journal (1992)

Skeletal muscle myopathy is a well-known side-effect of systemically administered corticosteroids. In recent years renewed attention is being paid to the involvement of the respiratory muscles and its consequent significance in pulmonary patients. Two different clinical patterns of steroid-induced muscular changes are known. In acute myopathy and atrophy after short term treatment with high doses of steroids, generalized muscle atrophy and rhabdomyolysis occur, including the respiratory muscles. Chronic steroid myopathy, occurring after prolonged treatment with moderate doses, is characterized by the gradual onset of proximal limb muscle weakness and may be accompanied by reduced respiratory muscle force. Animal studies demonstrated diaphragmatic myopathy and atrophy similar to the alterations in peripheral skeletal muscles. Fluorinated steroids induced selective type IIb (fast-twitch glycolytic) fibre atrophy, resulting in changes in contractile properties of the diaphragm. Non-fluorinated steroids may also induce histological, biochemical and functional alterations in the diaphragm. Observations in patients with collagen vascular disorders and with asthma and chronic obstructive pulmonary disease (COPD) underline the potential hazards of treatment with corticosteroids to respiratory muscle structure and function.
THE ISOLATION AND PROPERTIES OF THE SPECIFIC CYTOPLASMIC GRANULES OF RABBIT POLYMORPHONUCLEAR LEUCOCYTES
Authors: Zanvil A. Cohn, James G. Hirsch
Journal: The Journal of Experimental Medicine (1960)

A method has been described for isolation of the specific cytoplasmic granules of rabbit polymorphonuclear leucocytes. Homogeneous suspensions of leucocytes were disrupted by lysis in 0.34 M sucrose. This procedure liberated the cytoplasmic contents of the cell and dissolved a considerable proportion of the nuclei. Following disruption, the sucrose lysate was separated into three fractions by differential centrifugation, i.e. 400 g or nuclear pellet, 8,200 g or granule pellet and the postgranule supernate. Microscopic examination revealed that the 8,200 g pellet was composed of intact granules as well as occasional mitochondria. The other two fractions were morphologically heterogeneous. Studies with isolated granules demonstrated their lysis by a variety of weak acids and surface-active agents. When buffered solutions were employed between the ranges of pH 2.0 and 9.0, granule lysis began at pH 5.5 and was complete at pH 4.0. Chemical analysis disclosed that the granule pellet contained protein and phospholipid with only traces of nucleic acids. Approximately 70 to 80 per cent of the total cellular antimicrobial agent phagocytin was present in the granule fraction. This material was liberated from the granules by acid (pH 5.0 or lower). Studies on selected enzymes showed that acid phosphatase, alkaline phosphatase, nucleotidase, ribonuclease, deoxyribonuclease, and beta glucuronidase were predominantly localized in the granule fraction. Approximately 50 per cent of total cellular lysozyme and cathepsin were also present in the 8,200 g pellet. Disruption of the granules was associated with the release of the majority of granule protein and enzymes in a non-sedimentable form. The properties and composition of rabbit polymorphonuclear leucocyte granules seem to be analogous to those of liver lysosomes.
Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent
Authors: Kristen V. Khanna, Kevin J. Whaley, Larry Zeitlin, Thomas R. Moench, Karim Mehrazar, Richard A. Cone, Zhaohao Liao, James E.K. Hildreth, Timothy E. Hoen, Leonard Shultz, Richard B. Markham
Journal: Journal of Clinical Investigation (2002)

Because both HIV-1 virions and HIV-infected cells are present in the semen and cervical mucus of infected individuals, HIV-1 prevention strategies must consider both cell-free and cell-associated virus. Antibodies that target HIV-1 virions have been shown to prevent vaginal transmission of cell-free virus in macaques, but since cell-associated transmission has not been reliably demonstrated in this model system, no strategies to prevent such transmission have been tested. We have employed a mouse model in which SCID mice carry human peripheral blood leukocytes (HuPBLs). In these mice, vaginal transmission of cell-associated, but not cell-free, HIV-1 transmission occurs, mediated by transepithelial migration of HIV-infected cells. Topical application of β-cyclodextrin (β-CD), a cholesterol-sequestering agent that interferes with cell migration and budding of virus from lipid rafts, blocks transmission of cell-associated HIV-1. The HuPBL-SCID model of vaginal HIV-1 transmission should prove useful for investigating cell-associated HIV-1 transmucosal HIV-1 transmission, as well as for screening reagents for their potential efficacy in preventing sexual HIV-1 transmission.
Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy
Authors: Ronald J Buckanovich, Andrea Facciabene, Sarah Kim, Fabian Benencia, Dimitra Sasaroli, Klara Balint, Dionysios Katsaros, Anne O'Brien-Jenkins, Phyllis A Gimotty, George Coukos
Journal: Nature Medicine (2007)
Increased levels of urinary leukotriene E4 in children with severe atopic eczema/dermatitis syndrome
Authors: K. Øymar, L. Aksnes
Journal: Allergy (2004)

Background: Leukotrienes are thought to play a role in the pathogenesis of atopic eczema/dermatitis syndrome (AEDS). Urinary leukotriene E4 (U‐LTE4) is a marker of whole‐body cysteinyl‐leukotriene production. Aims of the study: To evaluate the role of leukotrienes in children with AEDS by measuring levels of U‐LTE4, and to evaluate whether levels of U‐LTE4 may reflect disease activity and allergic sensitization in AEDS. Methods: U‐LTE4 was measured by enzyme‐linked immunosorbent assay in 87 children with mild ( n = 32), moderate ( n = 34) and severe ( n = 21) AEDS, as well as in 72 nonatopic healthy controls. Fifty‐eight of the children with AEDS were sentitized to common allergens, and 29 were not. Results: Levels of U‐LTE4 were higher in children with severe AEDS (140; 66–166 μ g/mmol creatinine, median; quartiles) than in controls (52; 30–90, P &lt; 0.05), whereas levels of U‐LTE4 in moderate and mild disease were similar to controls. U‐LTE4 levels were similar in children with or without sensitization to common allergens, but severe AEDS children with sensitization had higher levels of U‐LTE4 than those without sensitization. Conclusion: The results suggest a role for leukotrienes in the pathogenesis of severe AEDS, and may support a role for leukotriene‐antagonists in the treatment of this disorder. Levels of U‐LTE4 may reflect the disease severity and sensitization to allergens in AEDS.
Association of body mass index in early adulthood and middle age with future site-specific cancer mortality: the Harvard Alumni Health Study
Authors: L. Gray, I.-M. Lee, H.D. Sesso, G.D. Batty
Journal: Annals of Oncology (2011)

BackgroundThe association between adiposity in early adulthood and subsequent development of specific malignancies is unclear. Further, the potential for mediation by adiposity in middle age has not been well examined. In a rare study, we investigated the association of body mass index (BMI) in early adulthood with mortality from several site-specific cancers.DesignIn the Harvard Alumni Health Study cohort, 19 593 males had a physical examination at the university between 1914 and 1952 (mean age: 18.4 years) and returned a questionnaire in 1962 or 1966 (mean age = 45.1 years). BMI was computed using weight (kg)/height2 (m2) at both time points. Vital status follow up continued for a maximum of 82 years.ResultsPositive early adulthood cancer mortality gradients by BMI were found for all malignancies combined (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI]: 1.05–1.17 for a one standard deviation increase in early adulthood BMI), and for lung (HR = 1.24; 95% CI = 1.10–1.40) and skin (HR = 1.29; 95% CI = 0.96–1.75) cancers. There were also apparent associations for cancers of the oesophagus and urogenital sites. Mediation by BMI in middle age was found to be minimal.ConclusionHigher BMI in early adulthood appears to be a direct risk factor for selected malignancies several decades later.
Impaired memory and learning abilities in patients with systemic lupus erythematosus as measured by the Rey Auditory Verbal Learning Test
Authors: D Paran, I Litinsky, I Shapira-Lichter, S Navon, T Hendler, D Caspi, E Vakil
Journal: Annals of the Rheumatic Diseases (2008)

The purpose of this study was to assess and characterise verbal memory impairment in patients with systemic lupus erythematosus (SLE) by the Rey Auditory Verbal Learning Test (Rey AVLT).40 consecutive, unselected patients with SLE were evaluated with the Rey AVLT, a clinical and research tool for the study of multiple learning and memory measures. All patients were assessed for disease activity, damage, presence of antiphospholipid antibodies and depression. Findings were compared with those of 40 healthy controls matched for age, sex and education.The study group included 40 patients with SLE (37 females, 3 males), median age 33 years (range 20-59), median disease duration 8 years (range 0.3-32). The median disease activity measured by the SLE Disease Activity Index (SLEDAI) was 4 (range 0-16). Median damage measured by the SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) damage index score was 0 (range 0-4). Depression was detected in 16/40 patients. Several aspects of the memory domain, as measured by the Rey AVLT, were impaired in the SLE group, using analysis of variance with repeated measures. The learning curve of patients with SLE was significantly less steep compared with that of controls, (p = 0.036), the rate of words omitted from trial to trial was higher in the SLE group (p = 0.034) and retrieval was less efficient in SLE compared with controls (p = 0.004). The significance of these findings was maintained after omitting patients with stroke or depression.Learning ability was impaired in patients with SLE with a poor and inefficient learning strategy, as reflected by an impaired learning curve, repeated omissions and impaired retrieval. This pattern of memory deficit resembles that seen in patients with frontal lobe damage and warrants further localising brain studies.
Skin Prick Testing and the Use of Histamine References
Authors: H.‐J. Malling
Journal: Allergy (1984)

The skin prick test is a fundamental test in biological allergen standardization and in evaluation of changes in skin sensitivity due to treatment. The allergen concentration eliciting a wheal equal to that produced by histamine 1 mg/ml is generally accepted as the skin sensitivity. Using a standardized quantitative skin prick test, 25 mould allergic patients were tested with quadruplicate determinations of five 10-fold allergen concentrations of highly purified and standardized extracts. Histamine 1 and 10 mg/ml were used as positive references. The 10-fold increase of histamine resulted in a doubling of the histamine reaction and increased the mean wheal diameter from 4 to 7 mm. The correlation between skin sensitivity estimated by histamine 1 and 10 mg/ml is significant, but with a dissociation between the two ways of estimating the sensitivity of 0.25 log step in the low sensitivity range and 1.8 log step in the high sensitivity range (the difference at median sensitivity is 1 log step). No correlation was found between histamine- and allergen-induced wheal area increase, and the discrepancy might be caused by a difference in the endogenous histamine release and/or difference in the number of histamine receptors at different degrees of sensitivity. With the use of median values it is possible to perform biological standardization with histamine 10 mg/ml and interpolate to histamine 1 mg/ml. However, the response in individual patients varies, and because of the small wheal area and the low reproducibility with histamine 1 mg/ml we recommend the exchange of histamine 1 mg/ml to histamine 10 mg/ml as an international positive reference.
Neurobehavioral Disinhibition in Childhood Predicts Early Age at Onset of Substance Use Disorder
Authors: Ralph E. Tarter, Levent Kirisci, Ada Mezzich, Jack R. Cornelius, Kathleen Pajer, Michael Vanyukov, William Gardner, Timothy Blackson, Duncan Clark
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: This longitudinal study had three aims: 1) determine the extent to which boys at high average risk and low average risk for substance use disorder differ on a construct of neurobehavioral disinhibition, 2) evaluate the capacity of neurobehavioral disinhibition to predict substance use frequency at age 16, and 3) demonstrate the utility of neurobehavioral disinhibition in predicting substance use disorder. METHOD: The authors derived an index of neurobehavioral disinhibition from measures of affect, behavior, and cognition. The neurobehavioral disinhibition score was used to discriminate youth at high and low average risk for substance use disorder and to predict substance use frequency after 4–6 years and substance use disorder after 7–9 years. RESULTS: The neurobehavioral disorder score significantly discriminated boys at high average risk from those at low average risk at ages 10–12. Neurobehavioral disinhibition at age 16, in conjunction with substance use frequency and risk status group, predicted substance use disorder at age 19 with 85% accuracy and accounted for 50% of the variance in Drug Use Screening Inventory overall problem density score. Neurobehavioral disinhibition was a stronger predictor of substance use disorder (odds ratio=6.83) than substance consumption frequency (odds ratio=3.19). CONCLUSIONS: Cross-sectional and longitudinal analyses indicated that neurobehavioral disinhibition is a component of the liability to early age at onset of substance use disorder.
Estrogens and antiestrogens stimulate release of bone resorbing activity by cultured human breast cancer cells.
Authors: A Valentin-Opran, G Eilon, S Saez, G R Mundy
Journal: Journal of Clinical Investigation (1985)

Patients with advanced breast cancer may develop acute, severe hypercalcemia when treated with estrogens or antiestrogens. In this study, we examined the effects of estrogens and related compounds on the release of bone resorbing activity by cultured human breast cancer cells in vitro. We found that the estrogen receptor positive breast cancer cell line MCF-7 releases bone resorbing activity in response to low concentrations of 17 beta-estradiol. Bone resorbing activity was also released in response to the antiestrogen nafoxidine. Other steroidal compounds had no effect on the release of bone resorbing activity. Estrogen-stimulated release of bone resorbing activity occurred with live bone cultures, but not with devitalized bones, indicating that the effect was bone cell mediated. The breast cancer cell line MDA-231, which does not have estrogen receptors, did not release bone resorbing activity in response to 17 beta-estradiol or nafoxidine. Release of the bone resorbing activity by MCF-7 cells incubated with 17 beta-estradiol was inhibited by indomethacin (10 microM) and flufenamic acid (50 microM), two structurally unrelated compounds that inhibit prostaglandin synthesis. Concentrations of 17 beta-estradiol and nafoxidine that caused increased release of bone resorbing activity by the breast cancer cells caused a four- to fivefold increase in release of prostaglandins of the E series by MCF-7 cells. These data may explain why some patients with advanced breast cancer develop acute hypercalcemia when treated with estrogens or antiestrogens, and why bone metastases are more common in patients with estrogen receptor positive tumors.
Uncool, unsmooth, unhealthy
Authors: L. Farrell
Journal: BMJ (1996)

The average general practitioner will see about five patients die of cancer each year and about two of these deaths will be from lung cancer; since I started practice here six years ago I've had six patients die with it, and it is one of the few cancers that a GP can become unpleasantly familiar with.

Lung cancer remains a modern epidemic. Most GPs already have a high index of suspicion for persistent respiratory symptoms—especially if there is a positive smoking history—but even so, most cases are diagnosed too late for anything except palliative treatment. The unique feature of …