tbuckley/cabot-search huggingface dataset:
Abstract 47: KRAS-mutation dependent effect of zoledronic acid in human NSCLC preclinical models
Authors: István Kenessey, Krisztina Kói, Mihály Cserepes, Judit Dobos, Balázs Hegedűs, József Tóvári, József Tímár
Journal: Cancer Research (2015)

Abstract In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor of both classic and target based therapy. In human malignancies bisphosphonate drugs are applied to treat or prevent formation of bone metastases. Nitrogen-containing bisphosphonates inhibit the posttranslational modification of small G-proteins (e.g. Ras, Rac, Rho) and thus may affect proliferation and migration. In our preclinical work, we investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRAS-expressing human NSCLC cell lines. In vitro cell viability was measured by MTT assay in H358, LCLC-103H, H1650 and H1975 cells. Apoptotic cell death was quantified by flow cytometric detection of sub-G1-fraction in propidium-iodide stained cultures. Furthermore, we investigated the in vivo effect of zoledronic acid in a SCID mouse subcutaneous xenograft model. The extracted tumors were examined by traditional histological methods and the proportion of proliferating tumor cells was determined by Ki67 labeling. KRAS-mutant H358 human NSCLC cell line showed relative resistance to zoledronic acid on proliferation, while human lung cancer cell lines carried wild type KRAS proved to be sensitive. Zoledronic acid improved the cytostatic effect of traditional anti-cancer agent cisplatin. Zoledronic acid did not induce significant apoptosis in NSCLC cell lines in vitro, rather the blockade of the cell cycle appeared. In in vivo subcutaneous animal model, zoledronic acid significantly reduced the weight of LCLC-103H xenograft tumor harboring wild type KRAS, furthermore, the treatment decreased the number of Ki67-labeled tumor. Zoledronic acid induced the expression of VEGF in LCLC-103H cells and stimulated in vivo angiogenesis. We concluded that in human NSCLC cells the antiproliferative effect of zoledronic acid dependended on KRAS-status (wild-type or mutant). The inhibitory effect of zoledronic manifested through the in vitro and in vivo blockade of cell cycle. The in vivo angiogenic effect of zoledronic acid supported cytostatic effect of cisplatin. Our preclinical investigation suggests that patients with wild type KRAS-expressing NSCLC could potentially benefit from aminobisphosphonate therapy. Citation Format: István Kenessey, Krisztina Kói, Mihály Cserepes, Judit Dobos, Balázs Hegedűs, József Tóvári, József Tímár. KRAS-mutation dependent effect of zoledronic acid in human NSCLC preclinical models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 47. doi:10.1158/1538-7445.AM2015-47
Irregular breathing during sleep in patients with panic disorder
Authors: M B Stein, T W Millar, D K Larsen, M H Kryger
Journal: American Journal of Psychiatry (1995)

The authors examined the nocturnal breathing patterns of patients with panic disorder to determine whether these individuals had respiratory irregularities at a time when anxiety was not manifest.Respiratory polysomnography was conducted on 14 medication-free patients with panic disorder and 14 healthy comparison subjects. Semiautomated indices of ventilatory variability were calculated for representative 3-minute, artifact-free sleep samples, and manually scored indices of irregular breathing were rated (blind to diagnosis) for the entire last 2 nights of sleep.Patients with panic disorder had evidence of abnormal sleep breathing as indicated by increased irregularity in tidal volume during REM and an increased rate of microapneas (i.e., brief [5-10-second] pauses in breathing). A subgroup of patients (including some with recent sleep panic attacks) had indices of subtle disorders in breathing during sleep that were above the 95th percentile for the comparison subjects.These findings extend the observations in the awake state that patients with panic disorder breathe more irregularly than healthy comparison subjects. The irregularities may be attributable to altered brainstem sensitivity to CO2 or to other as yet unexplained factors. A possible relationship between irregular nocturnal breathing and sleep panic attacks is discussed.
Thyroid nodules and polymorphic variants in the RET proto-oncogene, GFRA1 and DNA repair-related genes among Kazakh and Russian populations exposed as children to nuclear fallout near Semipalatinsk, Kazakhstan
Authors: Alice J. Sigurdson, Charles E. Land, Marbin Pineda, Zhanat Carr, Boris I. Gusev, Zhaxibay Zhumadilov, Joni L. Rutter, Elaine Ron, Jeffery P. Struewing
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1490 

Ionizing radiation exposure during childhood is the only well-established environmental risk factor for thyroid cancer, but this exposure cannot explain more than a small fraction of the observed variation in risk, suggesting genetic variability may play a role. However, the relative rarity of thyroid cancers is problematic for accruing large numbers of cases. Because thyroid nodules represent an intermediate endpoint related to thyroid cancer risk, we evaluated nodules and several polymorphisms in pathways potentially relevant to thyroid tumorigenesis, including the RET proto-oncogene, DNA repair, and growth factor genes. The thyroid nodules were diagnosed by ultrasound screening in 1998 among 2998 persons living near the Semipalatinsk nuclear test site in Kazakhstan who were younger than 20 during the period of weapons testing (1949-1960). A total of 920 persons with thyroid nodules were found (cases). We conducted a nested case-control study within the cohort by frequency matching (1:1) those without nodules (controls) to cases by ethnicity (Kazakh or Russian), gender, and age at the time of examination in 5 year strata. Genomic DNA was obtained from stored Guthrie cards originally used for thyroid stimulating hormone (TSH) analysis and then anonymized. We analyzed 18 single nucleotide polymorphisms (SNPs) within 10 genes using Taqman 5′-nuclease assays. Logistic regression was used to calculate odds ratios (OR) and 95% Confidence Intervals (CI). Elevated thyroid nodule risks were associated with RET S836S (CT vs CC, OR = 1.5; 95% CI, 1.1-2.1), and GFRA1 193C>G (CG vs CC, OR=1.8; 95% CI, 1.0-3.2). Decreased risks of thyroid nodules were associated with RET A45A (AG vs. AA, OR = 0.8; 95% CI, 0.7-1.0 and for GG vs. AA, OR = 1.0, 95% CI, 0.7-1.3), XRCC1 R194W (RW vs RR, OR=0.9; 95% CI, 0.7-1.1 and for WW vs. RR, OR=0.5; 95% CI, 0.3-0.9), and TGFβ1 T263I (TI vs. TT, OR=0.5; 95% CI, 0.3-0.8). Similar results were found for RET S836S (CT vs CC, OR = 4.4; 95% CI, 1.7-11.4) and GFRA1 193C>G (CG vs CC, OR = 4.0; 95% CI, 0.9-18.4) for the small number of prevalent thyroid cancers (n=25) compared to controls. Other factors considered, such as thyroid volume, weight, TSH level, external or internal thyroid radiation dose or the matching variables (ethnicity, age, and gender), had no effect on the genotype point estimates in multivariable logistic regression analyses. Results of this study suggest that polymorphic variants in the RET proto-oncogene or RET- related genes may play a role in the etiology of thyroid nodules and possibly thyroid cancer. This work was supported by a Charles Harkin award for research in thyroid cancer.
The nature of general practice
Authors: A. Moore
Journal: BMJ (1996)

EDITOR,-The most important focus of our paper was to critically evaluate the assumptions that were required to make screening cost effective.'It would seem that Dr Borch-Johnsen and colleagues agree.Their paper, however, did not adequately examine the specificity and sensitivity of screening; furthermore it examined screening and treatment versus no specific treatment.'This latter approach should be considered obsolete since the effects of angiotensin converting enzyme inhibition to reduce progressive renal failure have been shown.3We concluded that the incidence ofhypertension before, at the onset of, or just after the development of microalbuminuria should be determined.We did not define hypertension.The level of blood pressure recommended for treatment is debated; some advocate that an increase in blood pressure from baseline is as important an indication for starting antihypertensive treatment as is a specific level.The difficulties with measuring blood pressure have long been identified; none the less, doctors diagnose hypertension every day and start treatment.If hypertension is diagnosed and treatment with an angiotensin converting enzyme inhibitor is started then there is no need to test for microalbuminuria.Regarding the low predictive value of micro- albuminuria, the model assumed that true microalbuminuria was predictive of renal failure (all patients eventually progressed).The positive predictive value of 0.3 referred to the appropriate diagnosis of a single test.The model's baseline assumption was a positive predictive value of 0.8.The authors' practice (multiple tests by more than one method) differs considerably from the consensus recommendations.4The authors say that microalbuminuria will flag persons at high risk, presumably for cardio- vascular disease.Markers for vascular disease now include homocysteinemia, insulin levels, and polymorphisms in a variety of genes.These tests for the most part add cost but provide little additional benefit unless specific, proved treat- ment is instituted.There was concern about the use of quality of life adjustments.We agreed with the authors' concerns.1There is much debate on this approach, but we felt that ignoring health preference status was a greater error.We welcome further studies in this area.
Abstract 5879: Vascular Smooth Muscle Cells Express ErbB Receptors and Migrate In Response to Neuregulin
Authors: April Kalinowski, Nadia Hedhli, Kerry S Russell
Journal: Circulation (2009)

It is currently believed that in the heart only endothelial cells express the ligand of erbB receptors neuregulin-1 (NRG, a member of the EGF family). We previously demonstrated that NRG leads to a...
Abstract 17147: Prognostic Significance of Atrial Fibrillation in Acute Coronary Syndromes. A Propensity Score Matching Analysis
Authors: Manuel Almendro-Delia, Maria Jose Valle-Caballero, Juan Carlos GarcIa-Rubira, Angel GarcIa-Alcantara, Jose BenItez-Parejo, Kristel Medina-Rodriguez, Ana Delia Ruiz-Dunhil, Javier Mendoza-Vazquez, Rafael Hidalgo-Urbano, Jose MarIa Cruz-Fernandez
Journal: Circulation (2012)

Introduction:  Conflicting data exits with respect to the prognostic implication and management of atrial fibrillation (AF) in acute coronary syndromes (ACS). Some studies suggest AF as a mortality confounding factor in ACS that reflects its association with heart failure. We sought to evaluate the real involvement of AF in mortality.   Methods:  We designed a prospective study of patients from 40 Andalucian centers, previously included in ARIAM registry (Analisis del Retraso en el Infarto Agudo de Miocardio) from 2001 to 2011. Non adjusted and Adjusted Cox multivariate models were conducted. Propensity score matching (PSM) analysis was performed to adjust baseline characteristic of AF group (AFg)   Results:  From 39237 patients analyzed, 2852 patients (7,3 %) presented AF. AFg were older (71±9,8 vs 63±12; p   Conclusions:  AF during ACS is associated with a higher rate of in-hospital complications and is an independent predictor of mortality. The occurrence of AF in the course of ACS should be considered as a factor with prognostic implications.
Commentary: Imaging in biliary obstruction
Authors: Adrian M K Thomas
Journal: BMJ (2004)

Mrs Prior was referred for ultrasonography after identification of abnormal liver function.1 Imaging of the liver and biliary tree is a common problem, and advances in ultrasonography, computed tomography, and magnetic resonance imaging have improved our diagnostic ability.2 Ultrasonography is the first investigation for suspected biliary disease. This patient's scan showed stones in the gall bladder and in the lower common bile duct. Ultrasonography should be available with only a short wait for more urgent cases.

Her biliary tree is dilated with intrahepatic and extrahepatic biliary dilatation, and the common bile duct measured 11 mm. In over 95% of healthy people the diameter of the common bile duct is less than 4 mm. In patients with gall stones it can measure up to 7 mm without implying obstruction. The common bile duct can also dilate in elderly people secondary to degeneration in the ductal wall, reaching diameters of up to 9 mm, and change in size physiologically in relation to meals.

Mrs Prior had gall stones readily visible in the lower common bile duct on ultrasonography. However, even if the stones had not been visible, a diameter of over 10 mm would suggest their presence. Ultrasonography often fails to detect stones in the common bile duct, partly because of the presence of obscuring gas in the duodenum.3

The ultrasonogram also showed a swollen pancreas. Enlargement of the pancreas may have various causes, and if a stone is lodged in the distal common bile duct the patient may develop pancreatitis with pancreatic enlargement. The liver abnormalities were unexplained and caused concern. However, computed tomography excluded any disease.

Gall stones are common, with an incidence over 10% in the population. They are often found in patients who have no symptoms of gallbladder disease. In fact, patients can have appreciable radiological pathology with few if any symptoms. Mrs Prior will probably have had her stones for some time.
Growth arrest induced by anti-HER2 antibody blocks breast cancer cells in the late G1 phase of the cell cycle
Authors: Xiao-Feng Le, Weiqun Mao, Isabelle Bedrosian, Xianfeng Wen, Mollianne Murray, Khandan Keyomarsi, Mong-Hong Lee, Robert C. Bast
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2271 

Anti-HER2 antibody trastuzumab (Herceptin) has been used effectively to treat breast cancers that overexpress HER2. We and others have demonstrated that anti-HER2 antibodies suppress cancer growth primarily through induction of a cell cycle G1 arrest. We have also demonstrated that p27Kip1 upregulation is one of the key events that cause G1 arrest upon trastuzumab treatment. We have now shown that specific inhibition of CDK2 is another important event that contributes to induction of G1 arrest in SKBr3 and BT474 breast cancer cells that overexpress HER2. We have more precisely localized the position in the cell cycle where growth arrest occurs. Trastuzumab was able to dramatically inhibit the kinase activity and expression of CDK2, whereas the kinase activity and expression of CDK4 were not affected significantly by trastuzumab. Unlike p27Kip1 upregulation that occurs primarily through post-translational mechanism, CDK2 was downregulated at a transcriptional level indicated by Northern blotting and RT-PCR analysis. Moreover, trastuzumab effectively inhibited the promotor activity of CDK2. Trastuzumab decreased the kinase activity of cyclin E (because of CDK2 inhibition) although it had little effect on cyclin E expression. Overexpression of wild-type cyclin E or its more active lower molecular weight forms did not influence the response to trastuzumab. Cyclin D1 Expression was only affected by trastuzumab at late stages (after 24 hrs). Thus, trastuzumab preferentially targeted the CDK2-cyclin E complex during G1 phase. As a result, CDK2-cyclin E-induced Rb phosphorylation was more substantially inhibited by trastuzumab than CDK4-cylcin D-induced Rb phosphorylation. A marked reduction of CDK2-cyclin E activity and a modest reduction CDK4-cyclin D activity were associated with hypophosphorylated Rb protein so that more E2F1 was retained in Rb complex and that E2F1 activity was decreased. The differential effect of trastuzumab on CDK2 and CDK4 indicate trastuzmab-induced growth arrest occurs at late G1 phase of the cell cycle. This notion was further supported by examination of other cell cycle-dependent gene/protein expression. An early G1 marker c-Myc and a delayed-early marker ornithine decarboxylase were not significantly affected by trastuzumab treatment, whereas the late G1/S phase proteins DNA polymerase alpha and proliferating cell nuclear antigen were dramatically inhibited. These results suggest that growth arrest induced by anti-HER2 antibody blocks breast cancer cells in the late G1 phase of the cell cycle.
Abstract 2651: Major Bleeding is Associated with Increased Short-Term Mortality and Ischemic Complications in Non-ST Elevation Acute Coronary Syndromes: The ACUITY Trial
Authors: Steven Manoukian, Michele D Voeltz, Frederick Feit, Ramin Ebrahimi, Roxana Mehran, Eugenia Nikolsky, Jeffrey W Moses, A M Lincoff, Spencer B King, Gregg W Stone
Journal: Circulation (2006)
The novel potent PI3 Kinase inhibitors, PI-540 and PI-620: Activity in vitro and in vivo
Authors: Sonal Patel, Frederico Rojo, Letitia Lensun, Giles Pergl-Wilson, Nahid Saghir, Alexander Zhyvoloup, Anthony Robson, Florence Raynaud, Adrian Folkes, Paul Workman, Stephen Shuttleworth, Wendy Alderton
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

LB-192 

Phosphatidylinositol-3-kinases (PI3K) are lipid kinases that mediate cell signaling pathways controlling growth, proliferation, survival and motility. Deregulation of the PI3K/Akt pathway is important in tumour progression and a high frequency of mutations of the PI3K p110α isoform has been reported in human cancer (1). PI3K therefore represents an attractive therapeutic target. Previously we have described the identification of potent and selective inhibitors of PI3K (2, 3) and the discovery of second generation PI3K inhibitors with improved physicochemical properties (4). Here we reveal the structure of two prototypic inhibitors (PI-540, PI-620) and characterize the activity of these two compounds. PI-540 and PI-620 are selective Class 1A PI3K inhibitors which potently inhibit p110α at ~10nM and 7nM respectively. The anti-proliferative effects of PI-540 and PI-620 are in the low μM range, e.g.~ 1μM in A549 lung cancer cells. The evaluation of potential downstream PD markers of the PI3K pathway showed that both compounds caused a dose-dependent decrease in phospho-AKT (pAKT) phospho-S6 (pS6) and phospho-p70S6K in A549 lung, U87MG glioblastoma and PC3 prostate cancer cell lines whereas the constitutive levels of the respective total proteins remained unchanged. In vivo , PI-540 and PI-620 induced significant tumour growth inhibition in the A549 lung and DU145 prostate tumour xenograft models. No significant body weight loss was observed. Interestingly, in contrast to Western blot analysis of cell lines described above the whole tumour lysates did not show consistent reproducible knockdown of pAKT, phospho-p70S6K or pS6. However, preliminary immuno-histochemical analysis of formalin-fixed paraffin-embedded sections of DU145 tumour xenografts shows marked heterogeneous expression of the downstream marker pS6. In PI-540 and PI-620 treated tumours the pS6 levels was significantly reduced compared to control tumours. Studies are currently ongoing to evaluate other potential PD markers in tumours and surrogate tissues by both Western blotting and immuno-histochemical techniques. In summary, our data indicate that the lead chemical series exemplified by PI-540 and PI-620 potently and selectively targets PI3K signaling, exhibit anti-tumor activity in vivo and demonstrate inhibition of potential PD markers in vitro and in vivo and therefore warrant further optimization.    References: (1) Y. Samuels et al., Science, 2004 (2) S. Patel et al., Proceedings of the AACR (Abstract LB-247) 2004 (3 ) F. Raynaud et al., Cancer Research 2007 (4) K. Ahmadi et al., European Journal of Cancer Supplement, 2004
Ethical Debate: Case history: head injury and drunkenness
Authors: D. W Hodgkinson, A. J Gray
Journal: BMJ (1995)

Doctors in accident and emergency departments are sometimes presented with patients with potentially life threatening conditions who refuse to consent to treatment. The doctors then face a dilemma: to withhold necessary treatment or to act against a patient's express wishes. Two such cases are presented, and we asked a lawyer, two medical ethicists, a psychiatrist, and an accident and emergency physician to comment on the implications.
Abstract 186: microRNA-146a inhibits epithelial mesenchymal transition in non small cell lung cancer by targeting insulin receptor substrate 2
Authors: Ji Woong Son, Soo Young Lee, Moon Jun Na, Sun Jung Kwan, Hyo Sung Jeon
Journal: Cancer Research (2015)

Abstract BACKGROUND: During cancer progression, some tumor cells show changes in their plasticity by morphological and phenotypical conversions, as an expression of mesenchymal markers and loss of epithelial markers, collectively referred to as epithelial-mesenchymal transition (EMT). EMT has been increasingly recognized as a critical phenomenon in lung cancer progression. The goal of this study was to identify microRNAs involved in lung cancer progression. METHODS: A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in mesenchymal like lung cancer cells. The role of miR-146a in lung cancer progression was measured by invasion and migration assays in vitro. Bioinformatics and luciferase report assays were used to identify the target of miR-146a. RESULTS: The expression of miR-146a was reduced in mesenchymal like lung cancer cell lines. The over-expression of miR-146a induced a marked reduction of mesenchymal marker and increase epithelial marker in lung cancer cell lines. Moreover, the over-expression of miR-146a suppressed lung cancer cells migration and invasion. The expression of miR-146a was down-regulated in advanced lung cancer tissues. Insulin receptor substrate 2 (IRS2), an adaptor proteins that modulates normal growth, metabolism, survival, and differentiation, was identified as a target of miR-146a. miR-146a regulated the expression of IRS2 at the mRNA and protein levels. CONCLUSION: These data demonstrate for the first time that miR-146a suppresses lung cancer progression by repressing IRS2 expression. This provides a new insight into the post-transcriptional regulation of lung cancer progression by miRNAs, a potential approach for the treatment of lung cancer. Citation Format: Ji Woong Son, Soo Young Lee, Moon Jun Na, Sun Jung Kwan, Hyo Sung Jeon. microRNA-146a inhibits epithelial mesenchymal transition in non small cell lung cancer by targeting insulin receptor substrate 2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 186. doi:10.1158/1538-7445.AM2015-186