tbuckley/cabot-search huggingface dataset:
Phosphorylation by DNA-Dependent Protein Kinase Is Critical for Apoptosis Induction by Insulin-Like Growth Factor Binding Protein-3
Authors: Laura J. Cobb, Bingrong Liu, Kuk-Wha Lee, Pinchas Cohen
Journal: Cancer Research (2006)

Abstract Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) promotes apoptosis of cancer cells by both IGF-dependent and IGF-independent mechanisms. In vitro phosphorylation of IGFBP-3 by DNA-dependent protein kinase (DNA-PK) has been reported but with unknown functional relevance. Using a chemical inhibitor for DNA-PK in prostate cancer cells and a paired system of glioblastoma cell lines that either lack or express DNA-PK, we show that the apoptosis-promoting and growth-inhibitory actions of IGFBP-3 are completely abrogated in the absence of catalytically active DNA-PK. In the absence of DNA-PK activity, IGFBP-3 has reduced nuclear accumulation and is unable to bind its nuclear binding partner retinoid X receptor (RXR) α. We assessed the importance of the three potential DNA-PK phosphorylation sites in IGFBP-3 using PCR-based site-directed mutagenesis. When transfected into 22RV1 cells, IGFBP-3-S165A and IGFBP-3-T170A functioned in an identical manner to wild-type IGFBP-3 to induce apoptosis. In contrast, IGFBP-3-S156A was unable to promote apoptosis and exhibited reduced nuclear accumulation, suggesting a key role for DNA-PK-dependent phosphorylation in the regulation of IGFBP-3 action. These studies reveal a novel regulatory mechanism for the actions of IGFBP-3 in prostate cancer and show phosphorylation of Ser156 to be functionally critical in its apoptosis-inducing actions. (Cancer Res 2006; 66(22): 10878-84)
Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease
Authors: Shinji Tamura, Iichiro Shimomura
Journal: Journal of Clinical Investigation (2005)

Nonalcoholic fatty liver disease (NAFLD) is a component of the metabolic syndrome, with a clinical spectrum ranging from simple fatty liver to steatohepatitis, cirrhosis, and hepatocellular carcinoma. The primary event of NAFLD is the accumulation of triacylglycerols (TAGs) in hepatocytes. In this issue of the JCI, Donnelly et al. report on their use of stable isotope methodology to show that fatty acids stored in adipose tissue and fatty acids newly made within the liver through de novo lipogenesis are the major sources of TAGs in the liver and are secreted as lipoproteins in NAFLD.
Neurocognitive impairment in children with obesity and sleep disordered breathing
Authors: Ottavio Vitelli, Alessandra Tabarrini, Jole Rabasco, Nicoletta Pietropaoli, Anna Rita Mazzotta, Chiara Romano, Martina Forlani, Maria Pia Villa
Journal: European Respiratory Journal (2014)

Aims :To compare neurobehavioral disorders in children with Sleep-Disordered Breathing (SDB), with SDB and obesity and in normal controls.

Methods: We studied 36 children with SDB (Group 1: M/F 21/15; mean age 8.29±2.04 years, body mass index, BMI, percentile 62,61±29,65), 38 children with SDB and obesity (Group 2: M/F 27/11; mean age 8.73±1.69 years, BMI percentile 116,52±15,95) and 58 non obese control (Group 3: M/F 29/29; mean age 8.89±1.62 years).Groups 1 and 2 underwent clinical evaluation, overnight polysomnography, Attention Deficit/Hyperactivity (ADHD) rating scale and neurocognitive assessment based on Wechsler Intelligence Scale for Children (WISC-R). Group 3 underwent clinical interview and neurocognitive assessment.

Results .Verbal Intelligence Quotient (VIQ), Performance Intelligence Quotient (PIQ) and Full-Scale Intelligence Quotient (FSIQ) were lower in groups 1 e 2 than in controls (VIQ 98,11 ± 12,68 vs 91,78±16,11 vs 109,63±12,04; PIQ: 100.63±14.98 vs 93.92±14.89 vs 117.27±11.96; FSIQ: 96.75±13.51 vs 91.81±13.97 vs 114.93±11.05, respectively) (p<0.05).

Group 1 and 2 had 5/5 verbal subtest, 2/5 (group 1) and 4/5(group 2) nonverbal subtest significantly lower compared to controls.

A positive correlation between PIQ and age of onset of SDB (r= 0,335, p=0,04) was found in group 1. A positive correlation between VIQ and age of onset of SDB (r=0,335, p=0,05) and a negative correlation between VIQ and duration of SDB (r=-0,362, p=0,02) PIQ and BMI percentile (r=-0,341, p=0,03), FSIQ and Apnea/Hypopnea index (r=-0,321, p=0,05) were found in group 2.

Group1 had the highest hyperactivity score.

Conclusions .Obesity seems to be a cumulative risk factor for cognitive impairment in children with SDB.
Side population rather than CD133+ cells distinguishes enriched tumorigenicity in hTERT-immortalized primary prostate cancer cells
Authors: Jianjun Zhou, Honghe Wang, Virginetta Cannon, Karen Marie Wolcott, Hongbin Song, Clayton Yates
Journal: Molecular Cancer (2011)

Subpopulations of cancer cells with the capacity of generating solid tumors have been characterized. In various cancer types, including prostate cancer cells, a side population (SP) and CD133-expressing cells have been proposed as containing a population cancer cells with stem-like ability. Therefore the aim of this work was to determine, in prostate cancer cell lines, the frequency and tumorigenic potential of SP and CD133+ cells.In vitro 2D colony-forming assay and sphere-forming assay, Flow cytometry analysis and magnetic cell sorting were utilized to sort CD133+, CD133- and Side population (SP) cells. Our findings indicate that CD44 and integrin α-6 are uniformly expressed in the hTERT cell lines; however, CD133 is expressed only in a small population (< 0.1%). FACS-sorted CD133+ and CD133- cells exhibited similar tumorigenicity in vitro and in vivo. Additionally, for the hTERT cells, SP rather than CD133 expression showed an 8-fold enhanced tumorigenic potential. The data suggest that SP cells, rather than those with CD133 marker, contain the rare population of CSC capable of producing prostate tumors.Collectively, our data suggest that although CD133 is expressed only in a small population of hTERT-immortalized prostate cancer cells, it is not likely to be associated with stem cells, as CD133- and CD133+ cells exhibited similar tumorigenicity. However, SP isolated cells, appear to be enriched with tumorigenic stem-like cells capable of generating palpable tumors.
Gastric acid secretion and mucosal appearances in Addison's disease and hypopituitarism
Authors: A. W. M. Smith, I. W. Delamore, A. W. Williams
Journal: Gut (1961)

Studies of gastric acid secretion and mucosal appearances have been made in a group of 14 patients suffering from hypopituitarism. Achlorhydria was found in six of the patients suffering from Addison9s disease but in only one patient suffering from hypopituitarism. In both groups the mean gastric secretion of hydrochloric acid was considerably lower than in a group of control subjects and replacement therapy with cortisone and DOCA in Addison9s disease and cortisone and thyroid extract in hypopituitarism failed to restore gastric function to normal. A constant correlation was not found between gastric acid secretion and mucosal appearances.
Raised plasma adrenomedullin in patients with systemic sclerosis complicated by pulmonary hypertension
Authors: Y. NANKE
Journal: Annals of the Rheumatic Diseases (2000)

How should we manage fibromyalgia?We read with interest your leader, "How should we manage fibromyalgia?". 1 We were puzzled by Paul Reilly's statement that a comprehensive pain management programme...has the best chances of success, although even rheumatologists can practise amateur cognitive behavioural therapy in the clinic".Is Dr Reilly really suggesting that a rheumatologist's amateur eVorts oVer the best outcome for people with fibromyalgia?Dr Reilly oVers no evidence to support this statement.He does, however, find evidence to raise questions as to the value of patient self help groups.Dr Reilly cites a 1992 paper that reports an association between membership of such a group and worse prognosis in chronic fatigue syndrome. 2As the authors emphasised the caution with which the results should be interpreted, it is surprising that Dr Reilly has used this evidence to inform his clinical practice.Firstly, this is ancient research.Things have moved on.Although we would agree that some so called self help groups can end up as a circular review of symptoms, self management courses, which we at Arthritis Care espouse, are a very diVerent matter.Challenging Arthritis is a self management programme-and that title was chosen very deliberately.It is run by people with arthritis for people with arthritis.It gives people the skills to take control of their lives and their arthritis.It is practical and positive, and it works.The eVectiveness of similar programmes in the USA is well recorded. 3 Experience in the United Kingdom shows similar results, including better understanding of symptoms, improved communication with medical staV, and increased use of exercise and relaxation techniques.Probably most importantly of all, self management programmes significantly decrease pain, fatigue, and anxiety. 4 So it is extremely important to diVerentiate between navel gazing self help systems and courses such as ours, which encourage people to take control for themselves-and which work.Similar courses run on the Challenging Arthritis model are now available to people with other chronic conditions.Given Dr Reilly's desire to disabuse patients of the notion that their fibromyalgia is his problem alone, shouldn't eVective courses which encourage people to take control for themselves be a welcome adjunct to his treatment, even if it is run by a patient self management group?ROBINA
A dimethoxynaphthalene derivative (RS-43179 gel) compared with 0.025% fluocinolone acetonide gel in the treatment of psoriasis
Authors: A. LASSUS, S. FORSSTROM
Journal: British Journal of Dermatology (1985)

Thirty patients were entered into a double-blind trial comparing a dimethoxynaphthalene derivative (RS-43179 gel) and fluocinolone acetonide (Synalar gel) in the treatment of psoriasis. The two preparations were applied three times daily for 4 weeks, and the patients were assessed at weeks 1, 2, 3, 4, 7 and 9. No significant differences between the two preparations could be detected. By the end of the 4-week treatment period, the number of patients showing a 'Good, Excellent or Clear' therapeutic response was 25 out of 28 after RS-43179 treatment and 26 out of 28 after Synalar treatment. Four patients experienced irritation on the side treated with RS-43179. In two of these patients the reaction was severe and the treatment was discontinued, but in the other two patients, the local irritation was only moderate. No other adverse reactions were seen.
Preferential reduction of quadriceps over respiratory muscle strength and bulk after lung transplantation for cystic fibrosis
Authors: C Pinet
Journal: Thorax (2004)

<b>Background:</b> In the absence of complications, recipients of lung transplants for cystic fibrosis have normal pulmonary function but the impact of the procedure on the strength and bulk of respiratory and limb muscles has not been studied. <b>Methods:</b> Twelve stable patients who had undergone lung transplantation for cystic fibrosis 48 months earlier (range 8–95) and 12 normal subjects matched for age, height, and sex were studied. The following parameters were measured: standard lung function, peak oxygen uptake by cycle ergometry, diaphragm surface area by computed tomographic (CT) scanning, diaphragm and abdominal muscle thickness by ultrasonography, twitch transdiaphragmatic and gastric pressures, quadriceps isokinetic strength, and quadriceps cross section by CT scanning, and lean body mass. Diaphragm mass was computed from diaphragm surface area and thickness. <b>Results:</b> Twitch transdiaphragmatic and gastric pressures, diaphragm mass, and abdominal muscle thickness were similar in the two groups but quadriceps strength and cross section were decreased by nearly 30% in the patients. Patients had preserved quadriceps strength per unit cross section but reduced quadriceps cross section per unit lean body mass. The cumulative dose of corticosteroids was an independent predictor of quadriceps atrophy. Peak oxygen uptake showed positive correlations with quadriceps strength and cross section in the two groups, but peak oxygen uptake per unit quadriceps strength or cross section was reduced in the patient group. <b>Conclusions:</b> The diaphragm and abdominal muscles have preserved strength and bulk in patients transplanted for cystic fibrosis but the quadriceps is weak due to muscle atrophy. This atrophy is caused in part by corticosteroid therapy and correlates with the reduction in exercise capacity.
Oxidative Capacity of Atherosclerotic Tissue of Rabbit and Dog, With Special Reference to Succinic Dehydrogenase and Cytochrome Oxidase
Authors: NELICIA MAIER, HENRY HAIMOVICI
Journal: Circulation Research (1965)

The oxidative capacity of the succinic oxidase and cytochrome oxidase systems, as measured by the oxidative response to succinate and p -phenylenediamine was studied in slices of aortas from rabbits and dogs subjected to an atherogenic regimen, and in the liver as reference tissue. In both animals, at an early stage in the atherosclerotic process, the oxidative capacity of both systems was increased in the atherosclerotic intima-media layer, separated at the cleavage plane, while at a later stage it was decreased. The intima-media of the uninvolved portions of the aorta showed a decrease in the oxidative capacity of the cytochrome oxidase system, whereas that of the succinic oxidase system remained unchanged. The liver, although the site of massive deposition of lipids, in the rabbit particularly, showed no enzymatic changes at any time during the administration of the atherogenic regimen. These findings indicate that metabolic alterations of the arterial wall are associated with the development of atherosclerosis.
A Multi-Marker Approach to Predict Incident CKD and Microalbuminuria
Authors: Caroline S. Fox, Philimon Gona, Martin G. Larson, Jacob Selhub, Geoffrey Tofler, Shih-Jen Hwang, James B. Meigs, Daniel Levy, Thomas J. Wang, Paul F. Jacques, Emelia J. Benjamin, Ramachandran S. Vasan
Journal: Journal of the American Society of Nephrology (2010)

Traditional risk factors do not adequately identify individuals at risk for CKD. We related a multi-marker panel consisting of the following seven circulating biomarkers to the incidence of CKD and microalbuminuria (MA) in 2345 participants who attended the sixth Framingham Offspring Study examination (1995 to 1998): C-reactive protein, aldosterone, renin, B-type natriuretic peptide (BNP), plasminogen-activator inhibitor type 1, fibrinogen, and homocysteine. We defined CKD at follow-up (2005 to 2008) as estimated GFR (eGFR) <60 ml/min per 1.73 m²; we defined MA as urine albumin-to-creatinine ratio ≥25 (women) or 17 (men) mg/g on spot urine samples. We identified a parsimonious set of markers related to outcomes adjusting for standard risk factors and baseline renal function, and we assessed their incremental predictive utility. During a mean 9.5-year follow-up, 213 participants developed CKD and 186 developed MA. In multivariable logistic regression models, the multi-marker panel was associated with incident CKD (P < 0.001) and MA (P = 0.003). Serum homocysteine and aldosterone both were significantly associated with CKD incidence, and log-transformed aldosterone, BNP, and homocysteine were significantly associated with incident MA. Biomarkers improved risk prediction as measured by improvements in the c-statistics for both CKD and MA and by a 7% increase in net risk reclassification. In conclusion, circulating homocysteine, aldosterone, and BNP provide incremental information regarding risk for incident CKD and MA beyond traditional risk factors.
Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular Opossum Kidney Cells
Authors: Christoph Sauvant, Hildegard Holzinger, Michael Gekle
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. It was shown previously that EGF induces release of the important prostanoid prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) in proximal tubular opossum kidney (OK) cells and PGE<sub>2</sub> then stimulates initial basolateral uptake of organic anions (OA) dose dependently. PGE<sub>2</sub> is a receptor agonist and a known substrate for the basolateral exchanger mediating OA uptake (OAT1 and/or OAT3). This study investigated the mechanism of short-term PGE<sub>2</sub> action on initial basolateral OA uptake in OK cells. PGE<sub>2</sub> stimulation of OA uptake was abolished by selective inhibition of adenylate cyclase (by MDL-12, 330A) or protein kinase A (PKA; by H89). PGE<sub>2</sub> stimulation of OA uptake persisted after preloading the cells with glutarate and was still abolished by inhibition of PKA. Selective activation of adenylate cyclase by forskolin led to identical results. These data contradicted the hypothesis that PGE<sub>2</sub> action on OA uptake is due to its action as a counter ion. Therefore, we tested whether the PGE<sub>2</sub> receptors (EP1 to 4) are involved in stimulation of OA uptake in OK cells by PGE<sub>2</sub>. Because of their intracellular signaling profile, EP1 and EP3 were not taken into account as possible receptors for mediation of PGE<sub>2</sub>-induced OA uptake. With the use of selective agonists (11-deoxy PGE<sub>1</sub> and butaprost), EP4 was pharmacologically identified as the receptor responsible for PGE<sub>2</sub>-mediated stimulation of OA uptake. By reverse transcription–PCR, cloning, and subsequent sequencing, a homologue fragment to EP4 was identified in OK cells. EGF-induced stimulation of basolateral organic anion uptake was abolished by inhibition of adenylate cyclase or PKA. This indicates that EGF action is mediated by generation of PGE<sub>2</sub>. The following model is proposed: PGE<sub>2</sub> generated in the cells does not act as a counter ion but activates adenylate cyclase. This is mediated by a homologue of EP4 receptor. cAMP then activates PKA, which stimulates initial basolateral uptake of OA in OK cells by a not-yet-known mechanism. PGE<sub>2</sub> is an organic anion, a potential stimulator of organic anion excretion, and an important mediator of inflammation all at once. Thus, the mechanism presented here may contribute to a limitation of inflammatory events in the kidney cortex interstitium.
Primary in vitro cell-mediated lympholysis reaction of NZB mice against unmodified targets syngeneic at the major histocompatibility complex.
Authors: U Botzenhardt, J Klein, M Ziff
Journal: The Journal of Experimental Medicine (1978)

T-cell cytotoxicity of NZV mice was tested after in vitro sensitization against a group of H-2 identical strains (BALB/c, B10.D2, DBA/2, HW19). A highly significant and unexpected unidirectional cell-mediated lympholysis (CML) reaction by the sensitized NZB effector cells on these targets was found. After sensitization in vitro with stimulator cells of one H-2d strain, NZB effector cells (H-2d) lysed all other H-2d targets and to a lesser degree, some non-H-2d targets (C57BL/10, DBA/1, B10.Q, CBA, B10.S, A.SW). NZB targets were not lysed. Differences in the major histocompatibility region between NZB and other H-2d strains could be excluded as a possible explanation for the observed reaction of NZB (H-2d) against other H-2d strains. These results consequently represent the first description of a primary in vitro CML directed against determinants not coded for in the major histocompatibility complex. The responsible effector cells are demonstrated to be T cells. The CML of NZB against H-2 identiical targets appears best explained by a reaction against minor histocompatibility antigens. This, and the observed cross-reactions, would indicate that the cytotoxic T-cell system in NZB mice is not subjected to restrictions found in all normal mouse strains tested until now under similar conditions. It is suggested that this hyperreactivity is related to the autoimmune responsiveness of the NZB strain.
Sublethal Irradiation Induces Vascular Endothelial Growth Factor and Promotes Growth of Hepatoma Cells: Implications for Radiotherapy of Hepatocellular Carcinoma
Authors: Yih-Lin Chung, James Jer-Min Jian, Skye Hongiun Cheng, Stella Y.C. Tsai, Vincent P. Chuang, Thomas Soong, Yu-Mong Lin, Cheng-Fang Horng
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To investigate the clinical benefit of additional radiotherapy to patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE) and the molecular effects of radiation on gene expression in hepatoma cells. Experimental Design: Between August 1996 and August 2003, 276 and 64 patients with American Joint Committee on Cancer stage T3N0M0 hepatocellular carcinoma receiving TACE alone and TACE followed by three-dimensional conformal radiotherapy, respectively, at our institution were studied. Clinical outcome and pattern of failure were analyzed for the association of survival benefit with radiotherapy. The molecular effects of radiotherapy were studied in vitro and in vivo using human hepatoma cells with different p53 mutation and hepatitis B virus infection status. Results: Median follow-up and survival time in the TACE alone and TACE + radiotherapy groups were 39 and 19 months, and 51 and 17 months, respectively. Additional radiotherapy to TACE did not improve overall survival (P = 0.65). However, different failure patterns were noted after TACE and after radiotherapy. Although all irradiated tumors regressed substantially, radiotherapy rapidly enhanced both intrahepatic and extrahepatic tumor progression outside the radiotherapy treatment field in a significant portion of patients, which offset the benefit of radiotherapy on overall survival. In molecular analysis of the radiation effects on human hepatoma cells, radiotherapy rapidly induced p53-independent transcriptional up-regulation of vascular endothelial growth factor (VEGF), increased VEGF secretion in a dose-, time-, and cell type–dependent manner, and promoted hepatoma cell growth in vivo with enhanced intratumor angiogenesis, which correlated well with elevated levels of serum VEGF. Conclusions: Radiotherapy to eradicate a primary hepatocellular carcinoma might result in the outgrowth of previously dormant microtumors not included in the radiotherapy treatment field. Radiotherapy-induced VEGF could be a paracrine proliferative stimulus. Therapeutic implications of the study justify the combination of three-dimensional conformal radiotherapy with anti-VEGF angiogenic modalities for the treatment of unresectable hepatocellular carcinoma to reduce relapses.