tbuckley/cabot-search huggingface dataset:
Abstract LB-93: The role of GSK-3 in mammary gland development and oncogenesis
Authors: Joanna Dembowy, Jim Woodgett
Journal: Cancer Research (2011)

Abstract Glycogen synthase kinase 3, comprised of two isoforms: α and β, is a central regulator of several signaling pathways that play key roles in development and cancer. Chemical inhibition or genetic loss of GSK-3 in a normal mouse breast cell line cultured under conditions resembling the physiological breast environment resulted in morphological defects reminiscent of early stages of disease. A similar phenotype was also observed upon expression of an activated allele of β-catenin, a major GSK-3 target protein often mutated and elevated in human cancers. These findings implicate GSK-3 as a key regulator of normal ductal development, which may be disrupted early in cancer progression. Upon genetic deletion of GSK-3 (double knock-out of all four alleles, DKO) from breast tissues of mice, dams are unable to nurse their pups. These animals develop severe mammary intraepithelial neoplasia and squamous metaplasia frequently at first pregnancy. Following 4–6 months of continuous breeding, breast adenocarcinomas are observed with elevated levels of ß-catenin and Gli, along with increased expression of a putative mammary progenitor cell marker. Increased cell growth as well as expression of smooth muscle actin, a myoepithelial marker, are also features of these tumors. Similar developmental and functional defects are also observed in mice with breast glands lacking GSK-3 as well as ß-catenin (triple knock-out, TKO). The epithelium of TKO mammary glands undergoes various degrees of squamous differentiation and keratinization, although at a lower penetrance than the DKOs. Multiparious TKOs develop tumors, albeit with a longer latency (7–9 months). Preliminary flow cytometry analysis of mammary glands from DKO and TKO animals show the ratio of luminal to basal cell populations is increased in absence of GSK-3. We are currently investigating how GSK-3 may regulate mammary stem/progenitor cell commitment to these mammary cell lineages. Previously reported expression of stabilized ß-catenin in the mammary epithelium induces squamous metaplasia, but no adenocarcinomas were observed at 6 months. In our hands, these animals do develop small tumors at ∼10 months of age. These data suggest the observed DKO and TKO phenotypes are not solely mediated via aberrant ß-catenin signaling and that GSK-3 has ß-catenin-independent functions in mammary gland disease. Other pathways regulated by GSK-3 including Notch, Hedgehog and PI3K are being interrogated in DKO and TKO tumor-initiating cells to gain a molecular understanding of tumor development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-93. doi:10.1158/1538-7445.AM2011-LB-93
Abstract 51: Blood pressure lowering medications disrupt fatty acid metabolism in pancreatic cancer
Authors: Maheshwaran Sivarajah, SuhYueh Lim, Galina Chipitsyna, Qiaoke Gong, Tamer Aziz, Agnes Witkiewicz, Charles J. Yeo, Hwyda A. Arafat
Journal: Cancer Research (2010)

Abstract Despite the routine use of chemotherapy and radiotherapy, survival has not significantly improved in patients with pancreatic ductal adenocarcinoma (PDA), a situation that signifies the urgent need for novel therapeutic approaches. Angiotensin II (AngII), the principal hormone of the renin angiotensin system, is actively generated in the pancreas and has been suggested as a key mediator of PDA cell survival. Fatty acid synthase (FAS) is a key enzyme involved in synthesis of fatty acids and its high levels have been correlated with poor prognosis in many cancers. In this study, we investigated the potential molecular basis for the role of AngII in pancreatic carcinogenesis through studying its effect on FAS. AngII significantly increased the expression of FAS mRNA and protein in Panc-1 and PK9 PDA cells lines and induced FAS promoter activity. AngII-FAS mRNA induction was inhibited by an AngII type 1 receptor (AT1R) antagonist, losartan, and to a lesser extent by an AT2R antagonist. AngII activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the AngII-induced FAS synthesis. AngII activated the phosphorylation of AKT. Inhibition of AKT activation prevented the AngII-mediated increase of FAS. In human premalignant (n=6) and invasive PDA lesions (n=25), high expression levels of FAS correlated well with tumor stage and invasion status, and with high expression levels of angiotensin converting enzyme (ACE). Immunohistochemical staining of PDA serial sections show co localization of ACE with FAS in the malignant ducts and stromal cells. Oral administration of losartan significantly (p&amp;lt; 0.05) decreased the growth of PANC-1 and PK-9 cells xenografted on the flank of nude mice and significantly (p&amp;lt;0.05) reduced the expression of FAS mRNA and protein in the xenografts. Our data suggest a positive autocrine/paracrine action for the local pancreatic AngII generating system during pancreatic carcinogenesis, and provide the first insight into an AngII-initiated signal transduction pathway that regulates fatty acid metabolism and modulate lipogenesis in PDA. These results raise the possibility that AngII blockade therapies could be potential candidates in novel treatment strategies of PDA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 51.
PTU-186 Exogenous NSAID exposure increases transcriptional expression of the 5-lipoxygenase pathway in normal squamous tissue, but not in Barrett's metaplasia: an ex vivo study of oesophageal biopsy specimens
Authors: J Neale, C P C Boger, J Shutt, P Patel, J W Holloway, A P Sampson
Journal: Gut (2012)

<h3>Introduction</h3> Barrett9s oesophagus (BO) is a premalignant condition for oesophageal adenocarcinoma, an increasingly common malignancy with poor survival. The prostanoids and leukotrienes are lipid inflammatory mediators derived from a common precursor by the cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways respectively. Both families have been implicated in oesophageal adenocarcinoma, prompting studies of the effects on disease progression of drugs that modulate these pathways. NSAIDs may prevent tumorigenesis by inhibiting COX, but are also a risk factor for reflux and Barrett9s disease. Increased expression of 5-LO pathway proteins is implicated in oesophageal adenocarcinoma, so we hypothesised that in vitro exposure of oesophageal tissue to an NSAID may induce transcriptional expression of genes for 5-LO pathway enzymes. <h3>Methods</h3> Patients with known BO (n=14) were recruited as they attended endoscopy for routine surveillance. There was no evidence of dysplasia before or after this endoscopy. In each patient, oesophageal biopsies were taken from a single level of BO and from proximal squamous mucosa. Biopsies from each site were cultured for 15 h at 37°C in HEPES-buffered DMEM in the presence or absence of indomethacin (10 μM). Biopsies were then transferred to lysis buffer for quantification of mRNA for 5-LO, FLAP, LTA<sub>4</sub> hydrolase and LTC<sub>4</sub> synthase using quantitative RT-PCR. Transcript levels for each enzyme were calculated as mean ∆∆Ct values compared to baseline expression after correction with a calibration sample across all plates. <h3>Results</h3> Culture with indomethacin (10 μM, 15 h) significantly increased transcriptional expression of 5-LO (p&lt;0.01) and FLAP (p&lt;0.05) in squamous control biopsies, with a trend for increased LTC<sub>4</sub> synthase transcripts (p=0.08) but not LTA<sub>4</sub> hydrolase (p=0.38), suggesting induction of a cysteinyl-leukotriene biosynthetic pathway. Expression of the 5-LO pathway genes was elevated at baseline in Barrett9s tissues and in vitro exposure to indomethacin did not produce further changes in this group (all p&gt;0.2). <h3>Conclusion</h3> These results indicate that indomethacin increases transcriptional expression of the proximal, rate-limiting enzymes of the 5-LO pathway in squamous oesophageal tissues, which may lead to increased enzyme activity and production of tumorigenic leukotrienes. This preliminary study suggests that brief NSAID exposure in vitro may mimic changes in the expression of 5-LO pathway genes induced in vivo in Barrett9s metaplasia. <h3>Competing interests</h3> None declared.
Tc-99m Sestamibi Scintigraphy
Authors: S. KOUKOURAKI, P. PRASSOPOULOS, M. KOUKOURAKIS, A. VELIDAKI, N. KARKAVITSAS
Journal: Clinical Nuclear Medicine (2000)

An 80-year-old woman was hospitalized because of chest pain and dyspnea. A large mediastinal mass was shown on radiographs. Computed tomographic scans show a soft tissue mass in the upper anterior mediastinum. Fine-needle aspiration of the mass showed a malignant thymoma. The patient underwent radiotherapy after computed tomography–guided computerized treatment planning and received 64 Gy within 6.5 weeks (conventional fractionation). At the end of radiotherapy, new computed tomographic scans and MIBI scintigraphs were obtained. Both showed a necrotic area in the center of the mass as a result of its response to radiotherapy.
Intense and Diffuse Lung Uptake of 99mTc-MDP in a Patient With Pneumonia Associated With Secondary Hemophagocytic Lymphohistiocytosis
Authors: Leilei Yuan, Lanfang Zou, Chunlin Li, Jigang Yang
Journal: Clinical Nuclear Medicine (2014)

99mTc-methylene diphosphonate (MDP) bone scan was performed in a 49-year-old female patient who had non-Hodgkin lymphoma. 99mTc-MDP uptake was significant in both lungs. Bilateral bacterial pneumonia associated with secondary hemophagocytic lymphohistiocytosis was diagnosed after extensive examination.
PMO-097 Surgery for pancreatic cancer without preoperative biliary drainage: fiction in reality?
Authors: C Daker, N van Someren, K Besherdas
Journal: Gut (2012)

<h3>Introduction</h3> A recent article published in the New England Journal of Medicine describes decreased complication rate in patients who have not had preoperative biliary drainage of their obstructive jaundice caused by their pancreatic mass. Unfortunately our perception is such that the reality of early surgery without a bridging stent hangs in the realms of fantasy. Our aims were to analyse the outcome of patients diagnosed to have pancreatic cancer in clinical practice in North London. <h3>Methods</h3> In this duel centre retrospective study, a years worth of pancreatic cancer diagnoses was compiled using the North London Cancer Network Multi-disciplinary team meeting data base. The patients records were then searched gathering information on their dates of diagnosis; referral to our hepatobiliary surgeons at a local tertiary referral centre; whether they had a pre-operative stent; the date of their surgery (if they survived long enough to have it) and they9re ultimate outcome. <h3>Results</h3> 68 patients within our sector received a diagnosis (histological/endoscopic/radiological) of pancreatic cancer over the course of 1 year (May 2010–May 2011). Of this cohort 20 (29.4%) were referred for surgical opinion. During the lag between diagnosis and surgical review, 9 (45%) patients received endoscopic biliary drainage and stent insertion (all were 1st pass). The total number to ultimately receive their Whipple9s was 5 (25%). In four patients in whom surgery was felt to be an option, aggressive disease and complications leading to a lengthy in patient stay at the point of diagnosis meant that the physical condition of the patient had deteriorated to the point where they were no longer fit for surgery/inoperable. Only one patient proceeded straight to operation without prior stenting. Two patients had their operations privately. Unfortunately details of any post operative complications are not available. <h3>Conclusion</h3> Our experiences of pancreatic cancer is that at the point of diagnosis most cancers were inoperable 48 of 68 (70%). Within our study period only 5 of 68 (7%) patients had surgery for pancreatic cancer. The majority of patients even when initially considered for surgery (75%) do not end up having a resection. When patients are referred with symptoms of obstructive jaundice, knowing that the majority will not undergo surgery and also knowing in clinical practice that it is difficult to get surgical resection within 10 days of diagnosis, the humane thing to do instinctively is to stent and achieve biliary drainage. Achieving biliary drainage helps in improving the patients symptom profile and additionally allows chemotherapeutic options in those whose jaundice resolves. <h3>Competing interests</h3> None declared.
AB0348 Transcriptional Activity of Adipose Tissue May BE an Early Marker of Cardiovascular Risk in Rheumatoid Arhtritis
Authors: M. Nadali, R. Pullerits, M. Bokarewa, K. Andersson, S. Täryö Silfverswärd
Journal: Annals of the Rheumatic Diseases (2014)

Background Rheumatoid arthritis (RA) is an established risk factor for premature development of cardiovascular disease. Adipokines are signal molecules originating from adipose tissue and exhibit strong proinflammatory effects. We have previously shown that resistin utilizes IGF-1R and TLR4 pathway to induce inflammation in RA synovia. Objectives In the present study we evaluated the role of adipokines and adipokine-related genes on the cardiovascular risk in RA. Methods Cariovascular risk was estimated in 146 RA patients, all women (median age 57.5 years, range 21-71, median disease duration 8.0 years, range 1-49 years), using the modified Systematic Coronary Risk Evaluation (mSCORE). Serum levels of adipokines and IGF-1 were analyzed by ELISA. mRNA levels of IGF-1R, TLR4, Akt1, STAT3, RETN, and RELA (NF-kB) were analysed in peripheral blood leukocytes and in subcutaneous adipose tissue, using qPCR. The gene expression analysis was performed in the subgroup of younger RA patients (n=54, mean age 46 years, median mSCORE=1). The adipokine levels and gene expression were analyzed in relation to mSCORE. Results mSCORE was directly related on the age, disease duration, smoking habits and blood fat profile (cholestrol and triglycerides), and not to the DAS28 and BMI of RA patients. mSCORE correlated to the serum levels of leptin, resistin and visfatin. The patients with the increased cardiovascular risk (mSCORE≥1, n=86) had higher levels of adiponectin and visfatin, and low levels of IGF-1 and Akt1 mRNA in the peripheral blood leukocytes compared to the patients where cardiovascular risk was below detection level (mSCORE<1, n=56). In the subgroup of younger patients, serum resistin correlated to mSCORE and to the systemic inflammation but not to DAS28. Additionally, mSCORE showed a strong correlation to the adipocyte expression of resistin-triggering receptors (IGF1-R and TLR4) and to the mediators of their transcriptional signalling Akt, STAT3, and RELA. We observed no correlation between mSCORE and the transcriptional activity of the peripheral blood leukocytes. The correlation of mSCORE and transcriptional activity in adipocytes was not dependent on BMI and was stronger in the normal weight patients. Conclusions This pilot study shows a correlation between the cardiovascular risk and the transcriptional activity of the subcutaneous adipose tissue in women with RA. The expression of resistin-related genes in adipose tissue in younger women suggests that resistin may be a sufficient force supporting persistent transcriptional activity of adipocytes and driving premature cardiovascular disease in RA patients. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3893
INCIDENCE AND CLINICAL IMPACT OF LATE-ACQUIRED STENT FRACTURE AFTER SIROLIMUS-ELUTING STENT IMPLANTATION
Authors: Shoichi Kuramitsu, Hiroyuki Jinnouchi, Takashi Hiromasa, Yuhei Yamaji, Mizuki Miura, Yukiko Matsumura, Hisaki Masuda, Takenori Domei, Makoto Hyodo, Yoshimitsu Soga, Shinichi Shirai, Kenji Ando
Journal: Journal of the American College of Cardiology (2016)
P642The contribution of currents involving potassium ions in the formation of action potential in true pacemaker cells of mouse sino-auricular node
Authors: V Golovko, M Gonotkov
Journal: Cardiovascular Research (2014)

The experiments were carried out on male albino mice (n = 47). The slowest action potentials (dV/dt max 3±1 V/s (n = 27)) were recorded in the area of bifurcation of the sino-auricular(SA) node artery from the side of subendocardium. These cells had the longest spike-APs and the highest velocity of diastolic depolarization (DD). Such APs were determined by us as true pacemaker cells (Fig 1). Cs + (1 mmol) provided the greatest inhibitory effect on the duration and velocity of DD. The frequency of AP generation was reduced from 310±20 to 270±25 pulses per minute. Ivabradine (3 μmol) as an If current blocker slowed the velocity of DD two times. At the same time the frequency of AP generation was reduced by 24 % compared with the control. 4 AP in micromolar concentrations did not affect the action potential configuration of true pacemaker cells. 4 AP (1 mM) increased APD20 2 times and dV / dt 2-3 times, but did not have an effect on the duration and velocity the phase of final repolarization. The blocker of the rapid IKr E 4031 (0.5 mmol) lengthen APD90 and APD 100 by 25-30%. As a result, the frequency of AP generation was reduced by 28% due to elongation of spike-AP by 33% and the DD by 24%. The blocker cromanol 293B (5 mmol ) reduced the frequency of AP by 6-24 % due to lengthed of APD 90 and retardation of the velocity plateau phase by 18 % compared with the control.
Overview From the International Conference on Long-Term Tamoxifen Therapy for Breast Cancer
Authors: V. C. Jordan
Journal: JNCI Journal of the National Cancer Institute (1992)

The development of tamoxifen therapy to treat selected patients, with all stages of breast cancer, has provided the clinical community with an efficacious and safe drug for long-term therapy. Issues of safety are under constant review, but justified concerns about high doses of tamoxifen acting as a promoter of liver cancer in rats or as a promoter of endometrial cancer in women have not, as yet, proved to be of clinical relevance. The situation will continue to be reviewed during the development of the prevention studies in Europe and the United States because an improvement in women's health is the ultimate goal of these programs. The hallmark for the successful development of tamoxifen has been the close cooperation between the laboratory and the clinic. The clinical strategy of long-term tamoxifen therapy is a direct application of a laboratory concept. Furthermore, potential problems in the clinic have been identified in the laboratory, and the clinical community has responded quickly to evaluate the real risks to the patient population. This close cooperation will continue. Issues of drug resistance, new antiestrogen development, and the application of the knowledge about steroid receptors to develop targeted gene therapies are being addressed so that additional treatment approaches for breast cancer will be in place by the turn of the century.
A Controlled Double-Blind Evaluation of Hydroflumethiazide and Hydrochlorothiazide
Authors: Stephen G. Edelstein, Robert Flescher, Robert S. Morrison, Mindel C. Sheps, Frank A. Howard, Thomas C. Chalmers
Journal: New England Journal of Medicine (1961)

CHLOROTHIAZIDE and hydrochlorothiazide are potent diuretic agents, but the potassium loss induced by their routine use may cause serious side effects.1 It has now been clearly established that potassium depletion is at least partly responsible for the tendency of these drugs to induce hepatic coma in susceptible patients with cirrhosis.2 Hydroflumethiazide was introduced with the hope that this modification in the structure of hydrochlorothiazide might appreciably diminish the excessive loss of potassium without compromising the drug's effectiveness as a natriuretic agent.3 The present study was designed to determine whether hydroflumethiazide produces less urinary potassium loss than hydrochlorothiazide does for an . . .
“R-on-T” Phenomenon
Authors: P Oupadia, K Ramaswamy
Journal: New England Journal of Medicine (1998)

Figure 1. Ventricular fibrillation in an 83-year-old man after coronary angiography was caused by the “R-on-T” phenomenon, due to a sensing failure on the part of a temporary pacemaker with ventricular pacing, ventricular sensing, and an inhibition response. Paced beats (open arrows) are followed by four normal sinus beats (small arrows), and a paced beat then interrupts the downsloping portion of the T wave because of the failure of the pacemaker to sense the change (large arrow). This paced beat induces ventricular fibrillation. Immediate cardioversion was performed, and there were no sequelae. The patient, who had recently had a myocardial . . .
Lack of Evidence for Cancer Due to Use of Metronidazole
Authors: C. Mary Beard, Kenneth L. Noller, W. Michael O'Fallon, Leonard T. Kurland, Malcolm B. Dockerty
Journal: New England Journal of Medicine (1979)

Experimental studies have shown that metronidazole is carcinogenic in rodents and mutagenic in bacteria. In 771 women given metronidazole for the treatment of vaginal trichomoniasis, more cancers developed than had been expected after exclusion of carcinoma of one uterine cervix (observed, 24 cases; expected on the basis of the Connecticut Tumor Registry, 21.7; expected on the basis of the Third National Cancer Survey, 18.4). However, the excess was not statistically significant (P greater than 0.05). The observed and expected numbers of breast-cancer cases were the same, but four lung-cancer cases were observed, whereas 0.6 would have been expected. This finding is confounded by the fact that all four lung cancers developed in women who were smokers. Overall, we observed no appreciable increase in cases of cancer.