tbuckley/cabot-search huggingface dataset:
Abstract 2842: 5-aza-2’-Deoxycytidine induces cellular senescence in non-small cell lung cancer
Authors: Masashi Furukawa, Yuka Mimura, Hiroyuki Tao, Yusuke Mimura, Kazunori Okabe
Journal: Cancer Research (2016)

Abstract Background: Lung cancer is one of the refractory malignancies and the leading cause of cancer-related death worldwide. Although prognosis of lung cancer was improved by the anticancer drugs and molecular targeted therapies, the results are not sufficient. Cellular senescence is irreversible cell cycle arrest. The drug-dependent induction of cellular senescence in neoplastic cells is considered an important tumor suppressive mechanism. 5-aza-2’-deoxycytidine (5-aza-dC) causes cellular senescence in solid tumors. Hypermethylation of CpG islands is well known as a major inactivation mechanism of tumor suppressor genes such as E-cadherin. Loss of E-cadherin confers a poor prognosis in lung cancer patients and is associated with in vitro resistance to epidermal growth factor receptor inhibitors. This study was designed to assess the relationship of E-cadherin expression cellular senescence induced by 5-aza-dC in non-small cell lung cancer (NSCLC) cell lines. Materials and Methods: We investigated two NSCLC cell lines; H1299 and A549 reported they have hypermethylation in promoter lesion of E-cadherin. There are two clinically approved DNA methyltransferase inhibitors (DNMTi), 5-aza-dC and 5-azacytidine (5-aza-CR). We also used Sodium Butyrate (NaB). We treated them with each drug for 120 hours. Flow cytometry analysis, immunofluorescence staining for E-cadherin and senescence associated beta-galactosidase assays and immunoblotting for senescence related proteins assessed NSCLC cell outgrowth and morphology. Results: Both cell lines with 5-aza-dC or NaB treatment changed morphology and increased size but decreased cell numbers. 5-aza-CR causes apoptosis in both cell lines. In A549, E-cadherin expression increased after 5-aza-dC treatment. There is no E-cadherin expression in H1299 with or without treatment. Both cell lines with 5-aza-dC were positive for Senescence-associated beta-galactosidase staining, H3K9me3 and gamma-H2AX. Conclusion: Taking together these findings strongly suggest the ability of 5-aza-dC to induce cellular senescence in NSCLC cells. The cellular senescence induced by a 5-aza-dC approach has to be considered a therapeutic option for NSCLC and an important phenomenon to further investigate in the next future. Citation Format: Masashi Furukawa, Yuka Mimura, Hiroyuki Tao, Yusuke Mimura, Kazunori Okabe. 5-aza-2’-Deoxycytidine induces cellular senescence in non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2842.
Case 1-1964
Authors: John H. Knowles, Austin L. Vickery
Journal: New England Journal of Medicine (1964)

Presentation of CaseA fifty-five-year-old woman entered the hospital because of pulmonary nodules.Twenty-two years before admission a routine x-ray film of the chest (Fig. 1) showed a calcific lesion in the right lower lobe, three rounded calcifications at the left apex and multiple nodular densities in both lower lobes. Two years later a pleural effusion developed on the left side, and the patient entered a sanatorium; examinations of the sputum and guinea-pig inoculations were negative for tuberculosis, and she was discharged after three months. Thereafter, periodic x-ray films of the chest showed no change until five years before admission, . . .
Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial.
Authors: Simron Singh, Carlo Carnaghi, Roberto Buzzoni, Rodney F. Pommier, Markus Raderer, Jiri Tomasek, Harald Lahner, Juan W. Valle, Maurizio Voi, Lida Bubuteishvili-Pacaud, Jeremie Lincy, Carolin Sachs, Natsuko Okita, Steven K. Libutti, Do-Youn Oh, Matthew H. Kulke, Jonathan R. Strosberg, James C. Yao, Marianne E. Pavel, Nicola Fazio
Journal: Journal of Clinical Oncology (2016)

315 Background: In the groundbreaking, phase 3 RCT RADIANT-4 study, everolimus (EVE) significantly prolonged median progression-free survival (PFS) by 7.1 mo in patients (pts) with advanced, progressive, nonfunctional NET of GI or lung vs placebo (PBO); HR, 0.48 (95%CI, 0.35-0.67), P&lt;0.00001 [Yao JC et al, ECC-ESMO, 2015]. Methods: InRADIANT-4, pts with advanced, progressive, well-differentiated (G1/G2), nonfunctional GI or lung NET were randomized (2:1) to EVE (10 mg/d) or PBO. In this analysis, pts with NET of GI tract (stomach, colon, rectum, appendix, caecum, ileum, duodenum, jejunum, or small intestine) and unknown primary were included. Results: Of 302 pts, 175 had GI NET (EVE [n=118], PBO [n=57]); 36 had NET of unknown primary (EVE [23], PBO [13]). In GI NET pts, median age was 63 y; females: 55%; G1/G2: 75%/25%; WHO PS: 0, 78% or 1, 22%; Caucasian: 73%. Similar baseline characteristics were observed in pts with NET of unknown primary. Ileum (41%), rectum (23%) and jejunum (13%) were the most common locations in GI subgroup. The table below lists prior treatments. In pts with GI NET, median PFS (95% CI) by central review (EVE vs PBO) was 13.1 (9.2-17.3) mo vs 5.4 (3.6-9.3) mo with an estimated 44% risk-reduction in favor of EVE (HR, 0.56; 95% CI, 0.37-0.84). In pts with NET of unknown primary, median PFS (95% CI) by central review (EVE vs PBO) was 13.6 (4.1-not evaluable) mo vs 7.5 (1.9-18.5) mo (HR, 0.60; 95% CI, 0.24-1.51). The most frequent G3/4 adverse events irrespective of drug-relationship reported in ≥5% pts in GI subgroup were diarrhea, hypertension, stomatitis, abdominal pain, fatigue, and acute renal failure. Conclusions: The present subgroup analysis of RADIANT-4 study demonstrated improvement in PFS with EVE for pts with GI NET, and suggests efficacy in NET of unknown primary, with an estimated 40% to 44% risk-reduction in favor of EVE vs PBO. Safety profile for EVE is consistent with that previously reported. Clinical trial information: NCT01524783. [Table: see text]
Abstract 5213: Remarkably stable sex-ratio in sporadic kidney cancer incidence
Authors: Ghislaine Scelo, Estelle Chanudet-van den Brink, Peng Li, Chanida Vinayanuwattikun, David C. Muller
Journal: Cancer Research (2016)

Abstract Background: Patterns of sex-disparity in cancer incidence can provide clues on risk factors and susceptibility to the disease. While known kidney cancer genetic syndromes follow an autosomal dominant inheritance and equally affect males and females, kidney cancer occurs predominantly outside a syndromic context (97% of cases are sporadic) and more commonly in males than females. Methods: We used cancer registry data from 10 registries around the world, from countries showing large variations in kidney cancer incidence in 2012 (from 5.2 to 16.7/100,000 person-years) and with at least 20 years of registration. Using age-standardized incidence rate (on the World population), we compared the male-to-female sex-ratio in incidence rates across registries and over time. We also evaluated whether the sex-ratio varied by categories of age at diagnosis. Finally, we compared the kidney cancer-specific mortality after diagnosis in males and females in 2,969 cases using Cox regression model. Results and interpretation: From 1985 to 2005, the sex-ratio was on average 2.0 and showed little variation across countries: it was 1.7 in Iceland; 1.8 in Australia and Finland; 1.9 in the UK and Norway; 2.0 in Singapore, Estonia, the Czech Republic, and the USA; and 2.1 in Slovenia. The sex-ratios were also remarkably stable in all registries over time, arguing against the role of known risk factors such as tobacco smoking to which the proportion of exposed women has evolved drastically in the last 50 years. In line with the autosomal dominant inheritance, sex-ratio was on average 1.0 in younger ages and progressively increased to stabilize from around 40 years old on. In particular the ratio remained stable at older ages, which suggests that estrogen levels are unlikely to account for the lower risk experienced by women. In contrast to the observed difference in incidence, our survival analysis showed similar survival rates in both sexes after adjustment for age and stage at diagnosis. Conclusion: Our results suggest that the difference in kidney cancer incidence rates between males and females are not due to varying prevalence of known risk factors or a protection by sex hormones. While the susceptibility to the disease varies, the tumor behavior seems similar in males and females as shown by similar survival rates. Citation Format: Ghislaine Scelo, Estelle Chanudet-van den Brink, Peng Li, Chanida Vinayanuwattikun, David C. Muller. Remarkably stable sex-ratio in sporadic kidney cancer incidence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5213.
Natural Course of the Subsequent Pregnancy after a Single Loss in Women with and without the Factor V Leiden or Prothrombin 20210A Mutations.
Authors: Michiel Coppens, Nienke Folkeringa, Margreet Teune, Karly Hamulyak, Jan van der Meer, Martin H. Prins, Harry R. Büller, Saskia Middeldorp
Journal: Blood (2006)
Maternal HIV infection influences the microbiome of HIV-uninfected infants
Authors: Jeffrey M. Bender, Fan Li, Shoria Martelly, Erin Byrt, Vanessa Rouzier, Marguerithe Leo, Nicole Tobin, Pia S. Pannaraj, Helty Adisetiyo, Adrienne Rollie, Chintda Santiskulvong, Shaung Wang, Chloe Autran, Lars Bode, Daniel Fitzgerald, Louise Kuhn, Grace M. Aldrovandi
Journal: Science Translational Medicine (2016)

Maternal HIV infection may affect the infant’s microbiome, and this may contribute to the increased morbidity and mortality of HIV-exposed, uninfected infants.
Abstract 3765: Induction of amineoxidases as a possible mechanism of action of tamoxifen metabolites
Authors: T. J. Thomas, Tuomo A. Keinanen, Mervi T. Hyvonen
Journal: Cancer Research (2016)

Abstract To elucidate the mechanism of action of endoxifen in breast cancer, we determined its effects on estradiol-mediated growth of ERalpha-positive MCF-7 cells. Endoxifen is the active metabolite of tamoxifen; the most widely used selective estrogen receptor modulator for anti-estrogen therapy for women with estrogen receptor alpha-positive breast cancer. Clinical trials recognized that tamoxifen was a prodrug and got converted to active metabolites in the human body. Earlier studies recognized 4-hydroxytamoxifen (4HT) as the active metabolite of tamoxifen, although recent studies showed that the concentration of endoxifen was up to 10-fold higher than that of 4HT in patients treated with tamoxifen. These metabolites are formed by the action of cytochrome P450 2D6 (CYP2D6). We used quantitative PCR analysis to examine the effects of endoxifen on estrogenic stimulation of early response genes, c-myc, c-fos and Tff1. Since the natural polyamines, putrescine, spermidine and spermine, play important roles in estrogenic function, we also measured the activities of enzymes in the polyamine biosynthetic/metabolic pathway: ornithine decarboxylase (ODC), S-adenosyl-L-methionine decarboxylase (AdoMetDC), spermidine/spermine N1-acetyltransferase (SSAT), spermine oxidase (SMO), and acetylpolyamine oxidase (APAO). Polyamine levels were quantified by high performance liquid chromatography. Our results showed that estradiol increased the proliferation of MCF-7 cells by 2- to 3-fold and endoxifen suppressed the effects of estradiol on cell growth. The expression of c-myc, c-fos and Tff1 genes was significantly increased by estradiol, while the addition of endoxifen suppressed estradiol-mediated increase in gene expression. Estradiol increased the activity of ODC and AdoMetDC, whereas endoxifen suppressed the activity of these enzymes. Endoxifen had no effect on SSAT activity, whereas it significantly increased activities of amineoxidases, SMO and APAO. Estradiol increased putrescine and spermidine levels and endoxifen inhibited this increase. There was no significant effect on spermine levels. These data suggest that endoxifen exerts its growth inhibitory effects on MCF-7 cells by suppressing the expression of estradiol-stimulated oncogenes and polyamine biosynthetic pathway. The antiestrogenic effect of endoxifen is also manifested through the stimulation of polyamine oxidase enzymes, SMO and APAO. These results indicate for the first time that the upregulation of SMO and APAO is important in the mechanism of action of endoxifen in breast cancer cells. Citation Format: T. J. Thomas, Tuomo A. Keinanen, Mervi T. Hyvonen. Induction of amineoxidases as a possible mechanism of action of tamoxifen metabolites. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3765.
Effect of multiparametric MRI of the breast on diagnostic accuracy.
Authors: Katja Pinker-Domenig, Pascal Baltzer, Wolfgang Bogner, Stephan Gruber, Peter Christian Dubsky, Zsuzsanna Bago-Horvath, Rupert Bartsch, Thomas Helbich
Journal: Journal of Clinical Oncology (2014)

11009 Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the breast has been the mainstay of breast MRI with an excellent sensitivity but limited specificity. Available data suggests that the use of other functional MRI parameters such as diffusion-weighted imaging (DWI) and proton MR spectroscopic imaging (1H-MRSI) may provide additional specificity. The aim of this study was to evaluate if multiparametric MRI using DCE-MRI, DWI and 1H-MRSI improves diagnostic accuracy in breast cancer diagnosis cancer in comparison to DCE-MRI alone and MP MRI with two parameters. Methods: One hundred and thirteen female patients (mean age, 52; range, 22–86) with an imaging abnormality (BI-RADS 0, 4-5) were included in this prospective IRB-approved study. Written informed consent was obtained in all patients. MP MRI of the breast at 3Tesla with DCE-MRI, DWI and 3D-1H-MRSI was performed. The likelihood of malignancy was assessed for DCE-MRI and MP MRI with two (DCE MRI and DWI) and three (DCE MRI DWI and 3D1H-MRSI) parameters separately. Histopathology was used as the standard of reference. Appropriate statistical tests were used to assess sensitivity, specificity and diagnostic accuracy for each assessment combination. Results: There were 74 malignant and 39 benign breast lesions. MP MR with three MRI parameters yielded significantly higher AUCs (0.936) in comparison to DCE-MRI alone (0.814) (p<0.001). MP MRI with just two parameters at 3T did not yield higher AUCs (0.808) than DCE-MRI alone (0.814). MP MRI with three parameters resulted in elimination of false-negative lesions and significantly reduced the false-positives (p= 0.002). Conclusions: MP MRI with three parameters increases the diagnostic accuracy in breast cancer diagnosis compared to DCE-MRI alone and MP MRI with two parameters.
169P Serum CA19-9 response is an early predictive marker for the efficacy of regorafenib in refractory metastatic colorectal cancer
Authors: A. Komori, H. Taniguchi, Y. Kito, S. Hamauchi, T. Masuishi, H. Hasegawa, S. Mitani, Y. Narita, S. Kadowaki, T. Ura, M. Ando, K. Mori, H. Yasui, K. Muro, K. Yamazaki
Journal: Annals of Oncology (2015)
Part 10.4: Hypothermia
Journal: Circulation (2005)

Unintentional hypothermia is a serious and preventable health problem. Severe hypothermia (body temperature <30°C [86°F]) is associated with marked depression of critical body functions that may make the victim appear clinically dead during the initial assessment. But in some cases hypothermia may exert a protective effect on the brain and organs in cardiac arrest.1,2 Intact neurologic recovery may be possible after hypothermic cardiac arrest, although those with nonasphyxial arrest have a better prognosis than those with asphyxial-associated hypothermic arrest.3–5 With this in mind, lifesaving procedures should not be withheld on the basis of clinical presentation.4 Victims should be transported as soon as possible to a center where monitored rewarming is possible.

When the victim is extremely cold but has maintained a perfusing rhythm, the rescuer should focus on interventions that prevent further heat loss and begin to rewarm the victim. These include the following:





For patients with moderate to severe hypothermia, therapy is determined by the presence or absence of a perfusing rhythm. We provide an overview of therapy here and give more details below. Management of the patient with moderate to severe hypothermia is as follows:
Abstract 4742: Comparison of enhancement of the antitumor effect of CDDP by PXR antagonists
Authors: Shuichi Kishimoto, Megumi Yasuda, Megumi Tomita, Yuki Yamane, Ryosuke Suzuki, Shoji Fukushima
Journal: Cancer Research (2016)

Abstract We have already found that a nuclear receptor PXR can modulate the cytotoxicity of CDDP for cancer cells, and ketoconazole, a PXT antagonist, can be an agent enhancing the antitumor activity of CDDP due to increase of the intracellular platinum content as the mechanism. However, nuclear receptor ligands have a variety of functions, and there is a possibility that PXR antagonist may enhance the cytotoxicity of CDDP through the mechanism other than the inhibition of transporter-mediated efflux of CDDP. The goal of this study was to compare the enhancing ability of three PXR antagonists, ketoconazole (KTZ), phenethyl isothiocyanate (PEITC) and metformin (MFM), for the antitumor effect of CDDP and clarify the contribution of inhibition of the efflux transporter as the mechanism of PXR antagonist. Cell lines used in this study were human hepatoma cell line HepG2. Changes in mRNA expression were assessed by real-time RT-PCR, and the ability of apoptosis induction was assessed as caspase-3 activity. Total intracellular platinum contents were determined by ICP-AES. When HepG2 cells were treated for 24 hr with 10 μM of CDDP, no change of caspase-3 activity was observed when compared to control cells. Also, 30 μM of KTZ, 30 μM of PEITC or 5 mM of MFM had no affect on the caspase-3 activity in treated cells compared with control cells. When KTZ, PEITC or MFM was exposed to HepG2 cells from 24 hr before treatment and during 24-hr treatment with 10 μM of CDDP, the caspase-3 activity was significantly increased to 461%, 355% and 326% of the control, respectively, in comparison with that in CDDP alone. When HepG2 cells were treated for 8 hr with 25 μM of CDDP, the intracellular platinum content was 110 ng/mg protein. On the other hand when KTZ, PEITC or MFM was exposed to HepG2 cells from 24 hr before treatment and during 8-hr treatment with 25 μM of CDDP, the intracellular platinum content was apparently increased to 227%, 491% and 161% of CDDP alone, respectively. Three PXR antagonists resulted in an increase in the intracellular platinum content that seems to be due to inhibition of the platinum efflux transporter, but there is no correlation between increase in intracellular platinum content and enhancement of antitumor activity by PXR antagonists. These results concluded that PXR antagonist can be an agent enhancing the antitumor activity of CDDP, but the ability of PXR antagonist for enhancing antitumor activity of CDDP can not be determined from only the increase in the intracellular platinum content. Citation Format: Shuichi Kishimoto, Megumi Yasuda, Megumi Tomita, Yuki Yamane, Ryosuke Suzuki, Shoji Fukushima. Comparison of enhancement of the antitumor effect of CDDP by PXR antagonists. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4742.
Abstract 4217: First pre-clinical validation of radiogenomics in glioblastoma
Authors: Pascal Zinn, Sanjay Singh, Markus M. Luedi, Faramak Zandi, Aikaterini Kotrotsou, Masumeh Hatami, Ginu Thomas, Ahmed Elakkad, Joy Gumin, Erik P. Sulman, Frederick Lang, David Piwnica-Worms, Rivka R. Colen
Journal: Cancer Research (2016)

Abstract A plethora of Magnetic Resonance Imaging (MRI) features have been correlated to cancer genomics to date, however, none have established causality. Here, we present an in vivo xenograft RNA interference validated, potentially clinically applicable test method termed “Magnetic Resonance Radiomic Sequencing” (MRRS) for the noninvasive detection of cancer genomics in Glioblastoma. MRRS comprehensively assesses the entire tumor mass using imaging texture-based algorithms that generate thousands of variables (features) inherent to the tumor. Two independent glioblastoma stem cells (GSC1 and GSC3) harboring doxycycline inducible short hairpin RNA against Periostin (POSTN), a gene previously identified in our radiogenomic screen, were implanted at orthotopic location in nude mouse brain. In vivo knockdown of &amp;gt;90% and ∼40% POSTN gene was achieved in GSC3 and GSC1 respectively. The T2 and T1 post MRI texture features, in edema and contrast enhancement phenotype features were compared between doxycycline (POSTN knockdown) and sucrose (control) group of mice using T test statistics. The significant features were included in a Stepwise Forward Logistic Regression analysis to build the final predictive model. The accuracy of the model was tested using ROC cure analysis. Among 3600 features in GSC3 mice cohort, 117 features were significantly (p value&amp;lt;0.05) different between the two groups. The significant features were included in a Stepwise Forward Logistic Regression analysis, 2 textures features (feature 234 of edema T1 and feature 251 of edema T2) were selected to be included in the final predictive model. The AUC of the model with leave one out cross validation method was 100%. The similar analyses were done in the GSC1 mice. The final predictive model in the GSC1 group was statistically insignificant (p value = 0.15) with AUC (95% CI) = 73% (46%-98%), suggesting that MRRS is reflective of underlying gene expression levels. Our results therefore describe the ‘first mouse model derived MRRS signature to describe a causal link of gene alteration to MRRS. This novel test method may open an avenue for human-mouse matched co-clinical trials and noninvasive Radiogenomic diagnostics. Citation Format: Pascal Zinn, Sanjay Singh, Markus M. Luedi, Faramak Zandi, Aikaterini Kotrotsou, Masumeh Hatami, Ginu Thomas, Ahmed Elakkad, Joy Gumin, Erik P. Sulman, Frederick Lang, David Piwnica-Worms, Rivka R. Colen. First pre-clinical validation of radiogenomics in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4217.