tbuckley/cabot-search huggingface dataset:
Abstract 904: Lifetime genistein alters mammary tumors’ response to anti-estrogen tamoxifen treatment by affecting immune function in rats
Authors: Xiyuan Zhang, Katherine Cook, Leena Hilakivi-Clarke
Journal: Cancer Research (2015)

Abstract Consistent with the human data showing that soy intake reduces the risk of breast cancer recurrence, we have previously reported that childhood and lifelong genistein (GEN) intake enhanced response of mammary tumors to tamoxifen (TAM) treatment and prevented recurrence in rats. Mammary tumor recurrence was also inhibited by starting GEN consumption in adulthood. Since GEN is shown to alter immune functions, and tumor immune responses can determine cancer outcome, we examined several immune markers in the tumor prior to TAM treatment. Female Sprague-Dawley rats were fed control AIN93G diet or AIN93G diet supplemented with 500 ppm GEN either during childhood (between postnatal days 15 and 30), adulthood (from 55 days to end of the study), or both. Mammary tumors were induced by DMBA at the age of 48 days, and when a tumor reached a size of 1.4 cm in diameter (criteria for starting TAM treatment in the previous study), rats were euthanized (n = 15 per group), and blood and mammary tumors were collected. We determined the expression of CD8-alpha (present in cytotoxic T lymphocytes) and Foxp3, TGFβ1 and TGF2 (present in regulatory T-cells, Treg) in mammary tumors from rats with varying lifetime exposures to GEN. Compared with the control rats, expression of CD8-alpha mRNA was significantly increased by GEN intake at any time during the life cycle, suggesting an elevation in cytotoxic T-cells density infiltrating the tumor. Foxp3 and TGF-β1 mRNA were significantly reduced by GEN consumption. Increased Treg levels in tumors result in the suppression of immune responses; therefore, a reduction in Foxp3 and TGF-β1 may indicate a decrease in immune suppression. TGF-2 mRNA expression was significantly increased in the tumors of rats that consumed GEN only as adults. In the serum, interleukin (IL)-1 and IL-6 levels were significantly elevated in rats that consumed GEN only during childhood, whilst IL-6 was reduced in rats consuming GEN during lifetime or only as adults. IL-12 that is reported to stimulate cellular immunity, was increased in the rats that consumed GEN during lifetime or as adults. Our findings suggest that the ability of GEN intake to prevent mammary cancer recurrence is associated with improved immune responses in the tumor. Citation Format: Xiyuan Zhang, Katherine Cook, Leena Hilakivi-Clarke. Lifetime genistein alters mammary tumors’ response to anti-estrogen tamoxifen treatment by affecting immune function in rats. [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 904. doi:10.1158/1538-7445.AM2015-904
Lysosomal Enzyme Release by Vitamin A in L1210 Leukemia Cells 2
Authors: John O. Rundell, T. Sato, E. Wetzelberger, H. Ueda, D. Brandes
Journal: JNCI Journal of the National Cancer Institute (1974)

L210 lymphocytic leukemia cells in culture were treated with vitamin A alcohol. The maximum rate of vitamin A uptake occurred through 30 minutes' incubation. Release of lysosomal hydrolases by the vitamin was dose and time dependent, and the shift to unsedimentable activities peaked at ≈4 hours of incubation. The interval between maximum uptake and the peak of hydrolase release was considered the time required for structural or functional alterations responsible for the release phenomenon. Autoradiographic studies with labeled vitamin A showed incorporation into many cell structures, including mitochondria, Golgi, and nuclei, which suggests that sublethal and lethal damage induced by the vitamin in these cells alter these structures.
Novel potential for optimization of antitubercular therapy: Pulmonary delivery of rifampicin lipospheres
Authors: Charan Singh, L.V. Seshu Kumar Koduri, Arti Singh, Sarasija Suresh
Journal: Asian Journal of Pharmaceutical Sciences (2015)

The aim of the present work is to develop rifampicin loaded phospholipid lipospheres containing sulfphobutyl ether β-cyclodextrin and Vitamin C for inhalation to test their potential for deep lung delivery. The findings of the solid state characterization revealed the amorphous nature of the lipospheres. These exhibited a better flowability, an aerodynamic diameter in the range of 1.76 to 3.99 µm. Moreover, the fine particle fraction and emitted dose was found in the range of 68.84–83.73% and 80–93%, respectively. Moreover, lipospheres exhibited enhanced/equivalent efficacy in vitro in H37Rv strain. Hence, the results show the potential of lipospheres for pulmonary delivery of rifampicin.
Abstract 4371: Defective Inter-Domain Interaction within the Ryanodine Receptor Underlies a Common Pathogenic Mechanism of Heart Failure and Lethal Arrhythmia
Authors: Shigeki Kobayashi, Masafumi Yano, Hitoshi Uchinoumi, Takeshi Suetomi, Makoto Ono, Xiaojuan Xu, Hiroki Tateishi, Shinichi Okuda, Takeshi Yamamoto, Masunori Matsuzaki
Journal: Circulation (2008)
Epigenetic down-regulation of PGIS and the pathogenesis of NSCLC
Authors: M. Cathcart, S. G. Gray, N. Al-Sarraf, G. P. Pidgeon, J. V. Reynolds, K. J. O' Byrne
Journal: Journal of Clinical Oncology (2008)

14627 Background: Prostacyclin Synthase (PGIS) metabolizes the cyclooxygenase product, prostaglandin H(2), into prostacyclin (PGI2), a potent vasodilator and inhibitor of tumour cell aggregation and metastasis. PGIS over-expression inhibits the development of lung cancer in a murine model, implicating this enzyme as a target for chemoprevention. Hypermethylation of the PGIS promoter is implicated in colorectal cancer and NSCLC pathogenesis. This study examined PGIS expression and epigenetic regulation of the PGIS gene in NSCLC. The impact of PGIS expression on NSCLC tumour cell survival and invasiveness were also assessed. Methods: PGIS expression was examined in human NSCLC tumour samples and matched normal controls by western analysis and IHC. For epigenetic studies, cells were treated with either a DNA methyltransferase inhibitor (5-Aza-2-Deoxycytidine, 1 μM for 48 h) or a histone deacetylase inhibitor (trichostatin A, 250 ng/ml for 24 h) and PGIS expression was examined by RT-PCR. Chromatin immunoprecipitation (ChIP) studies of the PGIS promoter in response to TSA treatment were carried out using the Diagenode one-day ChIP Kit. Stable cell lines over- expressing PGIS under the control of a CMV promoter were generated. The effect of PGIS over-expression on tumour cell survival pathways was examined by BrdU (cell proliferation), FACS (apoptosis), and cell invasion assay. Results: PGIS was down-regulated or absent in human tumour tissue and protein samples relative to normal. Demethylation resulted in activation of PGIS expression. Histone deacetylase inhibitors significantly upregulated PGIS, with a concomitant increase in histone lysine acetylation at histones H3 and H4 around the PGIS promoter.Tumour cells over-expressing PGIS proliferated at a significantly (p<0.05) slower rate than null transfected controls, were less invasive, and more sensitive to apoptosis following serum-starvation. Conclusions: PGIS expression is down-regulated in NSCLC. PGIS transfection reduces proliferation and invasiveness, and increases apoptosis following serum-starvation. PGIS is epigenetically regulated by both DNA CpG methylation, and histone acetylation. Induction of PGIS or development of novel PGI2 analogues may be a novel strategy for future chemoprevention and treatment of NSCLC. No significant financial relationships to disclose.
Abstract 909: Mechanistic study of synergistic interaction between genistein and equol in MCF-7 human breast cancer cells in vitro
Authors: MISAKI ONO, KAORU EJIMA, MIKAKO TAKESHIMA, TAKAKO HIGUCHI, REI WAKIMOTO, SHUJI NAKANO
Journal: Cancer Research (2015)

Abstract Soy isoflavones, such as genistein, daidzein, glycitein and equol, a metabolite of daidzein, have been suggested to affect the growth of estrogen-receptor positive breast cancer cells in vitro, and thus considered to be involved in the prevention of breast cancer. We have recently reported that soy isoflavone component mixture has a greater preventive activity against breast cancer rather than genistein alone using chemically induced rat model of hormone-dependent mammary carcinoma. Therefore, we investigated here whether a synergistic interaction exists between genistein and other isoflavone components in estrogen receptor positive MCF-7 cells. Effects of genistein in combination with other isoflavone components on proliferation, apoptosis, cell cycle perturbation, and signal proteins for survival, proliferation, and apoptosis were evaluated by WST-1 assay, FACS analyses, and Western blotting. Synergistic anti-proliferative activity of genistein was observed in combination with three respective isoflavone components, with the most efficacious interaction observed in combination with equal. In FACS study, cells were arrested at the G2/M by genistein but G1/S by equol. However, when these components were combined, cells were arrested at the G2/M, indicating a dominant effect of genistein over equol. Although apoptosis was not evident when cells were treated with either genistein or equol alone, combination treatment markedly induced apoptosis, with demonstrable cleavage of PARP. Upon combination treatment, constitutive activities of Erk1/2 were enhanced, but those of Akt were significantly inhibited, with subsequent reductions of activities of downstream mTOR. Reduced expression of anti-apoptotic Bcl-xL and enhanced expression of proapoptotic Bax were also demonstrated. These data indicate that synergic mechanism of genistein in combination with equol would be mediated by enhanced apoptosis induction through inactivation of Akt and its downstream molecule mTOR, followed by subsequent upregulation of Bax and downregulation of Bcl-xL, thus providing mechanistic rationale for soy isoflavone for the prevention of human breast cancer. Citation Format: MISAKI ONO, KAORU EJIMA, MIKAKO TAKESHIMA, TAKAKO HIGUCHI, REI WAKIMOTO, SHUJI NAKANO. Mechanistic study of synergistic interaction between genistein and equol in MCF-7 human breast cancer cells in vitro. [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 909. doi:10.1158/1538-7445.AM2015-909
GTP as a biomarker of inosine monophosphate dehydrogenase (IMPDH) inhibition, in patients with advanced hematological malignancies treated with AVN944 in a phase I trial
Authors: K. Zuck, M. J. Choe, K. J. Strand, J. W. Strovel, J. Hamilton, D. K. Bol
Journal: Journal of Clinical Oncology (2008)

14515 Background: AVN944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate- limiting step in guanine nucleotide synthesis. Guanosine triphosphate (GTP) is the downstream product of IMPDH and levels of GTP are directly correlated with enzyme activity. Methods: This phase I study employed open-label dose escalations in patients (pts) with relapsed, refractory hematologic cancers with safety, pharmacokinetic (PK), pharmacodynamic, and efficacy endpoints. Between 12/05 and 12/07, a total of 117 cycles of AVN944 at 25 to 300 mg b.i.d. orally X 21d every 28d were administered to 60 pts. Peripheral blood mononuclear cell (PBMC) or leukemic blast samples were obtained from all pts pre and post-receiving AVN944 to determine effects on GTP pools, IMPDH activity and gene expression biomarkers. Nucleotide purification was accomplished by lysing PBMC followed by protein precipitation and C-18 ZIP TIP filtration. A novel LC-MS/MS method was developed and used to quantify the concentration of nucleotides. Results: The concentration of GTP was reduced in 79% of the patients after 4–8 hr of the first dose. The duration of GTP suppression higher than 50% was dose proportional at doses higher than 75 mg: 2.8 hr (100 mg), 6.3 hr (150 mg), 11.2 hr (200 mg), 13.8 hr (250 mg). This correlated with PK, which was also dose proportional. Longer GTP suppression correlated with IMPDH inhibition and gene expression biomarker movement. Conclusions: The new LC-MS/MS is a reliable method to quantify GTP suppression in clinical samples. The levels of GTP after AVN944 administration correlated with PK, enzyme activity, changes in gene expression, and disease stability. GTP is a promising biomarker for IMPDH inhibition and has potential clinical implications. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Avalon Pharmaceuticals Avalon Pharmaceuticals
A Case of Severe Gallstone Pancreatitis
Authors: K. Mergener, J. Baillie
Journal: Endoscopy (2000)

I am pleased to welcome as our Guest Discussant a former trainee of mine, and now a colleague, Dr Klaus Mergener, who is currently Chief of Endoscopy at the Johannes Gutenberg University Medical Clinic in Mainz, Germany. Dr Mergener developed a special interest in acute pancreatitis during his Advanced Endoscopy Fellowship at Duke University Medical Center, and has written a number of excellent papers and reviews on the subject. Welcome, Dr Mergener.
Lung cancer size and thoracic lymph nodes metastatic involvement: A correlation
Authors: Vesna Kosjerina Ostric, Zdravko Kosjerina, Goran Djenadic
Journal: European Respiratory Journal (2011)

Objective of the study was to determine the frequency of lymph node metastases depending on the lung cancer size.

Material of the investigation included 136 lung resection samples obtained on surgery of the lung cancer patients, 114 males and 22 females, at the mean 54.8 years of age.

Results and discussion: Squamous carcinoma was the most frequent lung cancer type (66.9%), followed by adenocarcinoma (27.2%), while small-cell (4.4%) and large-cell (1.2%) cancer types were more rarely found. Metastatic involvment of the lymph nodes was discovered in 80 (56.7%) of 136 examined lung resection samples. The total of 489 thoracic lymph nodes were examinated and metastases found in 207 (40.3%). The tumors sized 1.1-2 cm metastasized in 47% of the lymph nodes; the tumors sized 2.1-3 cm involved 32.7% of the lymph nodes by metastases; the tumors sized 3.1-4 cm metastasized in 36.3% of the thoracic lymph nodes; the tumors sized 4.1-5 cm involved 36% of the lymph nodes by metastases; the tumors in the size of 5.1-6 cm metastasized in 28.6% of the lymph nodes while those of over 6 cm in diameter involved 69% of the lymph nodes by metastases.

Conclusion: The number of lymph nodes involved by metastases does not increase with the size of the tumor of up to 6 cm; however, a further increase of the tumor size (over 6 cm in diameter) significantly increases the number of metastatic lymph nodes.
Abstract 323: High Incidence of Delirium in Survivors of Cardiac Arrest Treated with Mild Therapeutic Hypothermia
Authors: Jeremy S Pollock, Ryan Hollenbeck, Li Wang, Benjamin Holmes, Michael N Young, Eugene W Ely, John Mcpherson, Eduard Vasilevskis
Journal: Circulation (2014)

Background: Mild therapeutic hypothermia (TH) is a recommended treatment for comatose patients resuscitated from cardiac arrest. To our knowledge, the incidence of delirium and its associated risk factors has not been assessed in survivors of cardiac arrest treated with TH. Methods: Retrospective analysis was performed on 251 consecutive comatose survivors of cardiac arrest treated with TH from 2007 to 2013 at Vanderbilt University Medical Center following sudden cardiac arrest. The incidence and duration of delirium were measured in patients who awoke from coma after cardiac arrest and survived to ICU discharge. Delirium evaluations began after TH (temp >36 degrees Celsius), and were performed at least daily using the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the ICU. A multivariable logistic regression analysis was performed to examine the effect of cardiac arrest and post-arrest management characteristics (prior to warming) on delirium duration. This model adjusted for a...
Unexpected Role of PACE/Furin Cleavage Site in FVIII Biology: Implications for Hemophilia a Therapy
Authors: Joshua I Siner, Julie M Crudele, Courtney T Connolly, Shangzhen Zhou, Elizabeth P. Merricks, Timothy C. Nichols, Rodney M. Camire, Valder R. Arruda
Journal: Blood (2014)
CD148 Is a Membrane Protein Tyrosine Phosphatase Present in All Hematopoietic Lineages and Is Involved in Signal Transduction on Lymphocytes
Authors: Miguel Angel de la Fuente-Garcı́a, Josep Maria Nicolás, John H. Freed, Eduard Palou, Andrew P. Thomas, Ramón Vilella, Jordi Vives, Antoni Gayá
Journal: Blood (1998)
ACE2 activation improves pulmonary endothelial function and attenuates monocrotaline-induced pulmonary hypertension
Authors: Vinayak Shenoy, Altin Gjymishka, Katya Rigatto, Yanfei Qi, Chastity Bradford, Debra Ely, Michael Katovich, Mohan Raizada
Journal: European Respiratory Journal (2011)

Angiotensin converting enzyme 2 (ACE2), a member of the vasoprotective axis of the renin angiotensin system, protects the lungs against acute lung injury and pulmonary hypertension. The present study was undertaken to test the hypothesis that activation of endogenous ACE2 by diminazene aceturate (DIZE), a putative ACE2 activator would prevent and reverse monocrotaline (MCT)-induced pulmonary hypertension. In the prevention protocol, DIZE was administered at the same time as MCT, while for the reversal protocol DIZE was injected after 3 weeks of MCT administration. A single subcutaneous injection of MCT (50mg/kg) resulted in elevated right ventricular systolic pressure (RVSP) associated with the development of right ventricular hypertrophy (RVH). DIZE administration (15mg/kg per day s.c) significantly prevented increases in RVSP (Control: 31+3 mmHg; MCT: 57+7 mmHg; MCT+DIZE: 41+4 mmHg; n=5-8; p<0.05) and attenuated RVH (Control: 0.23+0.004 mmHg; MCT: 0.43+0.03 mmHg; MCT+DIZE: 0.26+0.01 mmHg; n=5-8; p<0.05). In subsequent studies, we observed a 63% decrease in acetylcholine-induced vasorelaxation of the pulmonary arteries from MCT challenged rats. DIZE treatment resulted in 50% improvement in acetylcholine-induced vasorelaxation, signifying better pulmonary endothelial function. Furthermore, DIZE treatment reversed MCT-induced increases in RVSP (Control: 33+2 mmHg; MCT: 78+6 mmHg; MCT+DIZE: 56+5 mmHg; n=7-11; p<0.05) and RVH (Control: 0.24+0.002 mmHg; MCT: 0.54+0.02 mmHg; MCT+DIZE: 0.44+0.03 mmHg; n=7-11; p<0.05). These data suggest that DIZE's primary protective effects are mediated by ACE2 activation, though other off-target effects may also contribute.
Incidence and Management Of Venous Thrombosis In Acute Leukemia: A Multicenter Study
Authors: Mariasanta Napolitano, Luca Valore, Giorgia Saccullo, Alessandra Malato, Calogero Vetro, Maria Enza Mitra, Alessandro Lucchesi, Francesco Fabbiano, Donato Mannina, Alessandra Casuccio, Francesco Di Raimondo, Sergio Siragusa
Journal: Blood (2013)
Abstract 2036: In Vivo Imaging of Protease Activity in Atherosclerosis Using A Near-Infrared Fluorescence Intravascular Catheter
Authors: Farouc A Jaffer, Matthias Nahrendorf, Claudio Vinegoni, Michael C John, Elena Aikawa, Mayu Uchihashi, Aloke V Finn, Vasilis Ntziachristos, Peter Libby, Herman K Gold, Ralph Weissleder
Journal: Circulation (2006)

Introduction: Augmented protease activity is a defining feature of vulnerable plaques. Here we demonstrate feasibility of imaging proteolytic activity in atherosclerosis using a custom-built intrav...
Platelets induce apoptosis via membrane-bound FasL
Authors: Rebecca I. Schleicher, Frank Reichenbach, Peter Kraft, Anil Kumar, Mario Lescan, Franziska Todt, Kerstin Göbel, Ingo Hilgendorf, Tobias Geisler, Axel Bauer, Marcus Olbrich, Martin Schaller, Sebastian Wesselborg, Lorraine O’Reilly, Sven G. Meuth, Klaus Schulze-Osthoff, Meinrad Gawaz, Xuri Li, Christoph Kleinschnitz, Frank Edlich, Harald F. Langer
Journal: Blood (2015)
Haloperidol plasma levels and clinical response: a therapeutic window relationship
Authors: T Van Putten, S R Marder, J Mintz, R E Poland
Journal: American Journal of Psychiatry (1992)

The purpose of the study was to assess the relationship between plasma haloperidol and clinical response.Sixty-nine newly admitted drug-free schizophrenic men were randomly assigned to receive haloperidol, 5, 10, or 20 mg daily for 4 weeks, and clinical response was measured at the end of the fixed-dose period. Haloperidol was assayed by a sensitive and specific radioimmunoassay.The authors found a curvilinear relationship between clinical response and plasma haloperidol during fixed-dose treatment, with an apparent optimum between 5 and 12 ng/ml. When plasma levels above 12 ng/ml were lowered to the 5-12 ng/ml range, all patients improved to varying degrees and no patient deteriorated. When plasma levels of nonresponders within this therapeutic window were raised above 12 ng/ml (as in routine practice), they, on balance, deteriorated in that they became more dysphoric. With the 20-mg dose, half the patients had plasma levels above 12 ng/ml.In this sample of newly admitted schizophrenic men, optimal clinical response occurred with a plasma haloperidol range of 5-12 ng/ml.
Prevalence and Growth Characteristics of Malignant Stem Cells in B-Lineage Acute Lymphoblastic Leukemia
Authors: Hikari Nishigaki, Chikako Ito, Atsushi Manabe, Masa-aki Kumagai, Elaine Coustan-Smith, Yuri Yanishevski, Frederick G. Behm, Susana C. Raimondi, Ching-Hon Pui, Dario Campana
Journal: Blood (1997)
Abstract 1460: Effect of HMR1766, a Soluble Guanylate Cyclase Activator, on Differentiation of Cardiac Fibroblasts and Extracellular Matrix Synthesis Induced by TGFbeta
Authors: Stephane C Illiano, Laurence Riva, Michele Bouloy, Philippe Beauverger, Stephen E O'Connor
Journal: Circulation (2006)
Development of a competitive hybridization/ELISA assay for the determination of GRN163 and GRN163L in plasma.
Authors: Allison C. Chin, Ning Go, Queenie Lam, David B. Karpf, Calvin B. Harley
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2043 

GRN163 and GRN163L are identical 13-mer thio-phosphoramidate oligonucleotides (the latter is lipid modified) that are potent and specific inhibitors of telomerase and which have shown efficacy in multiple human cancers in vitro and in vivo . Both compounds are completing IND-enabling preclinical studies. In order to support the advancement of one or both compounds into clinical development, a specific, accurate, precise and sensitive heterogeneous hybridization/enzyme-linked immunoabsorbent assay has been developed for the quantitation of thio-phosphoramidate oligonucleotides (GRN163 and its lipid-conjugated form, GRN163L) in plasma using a 96-well plate format. The principle of the assay is based on competitive binding of the analyte with a signal analogue for a complementary oligonucleotide sequence containing biotin at the 3’end. The resulting hybridization complexes are captured onto the surface of neutravidin-coated microtiter plates and signal detected using a fluorescence microtiter plate reader. Since the assay is competitive, the response is inversely proportional to the amount of GRN163 or GRN163L present in the sample. The assay is selective for the specific sequence tested, with a linear range of 0.2 to 4 nM. Intra- and inter-assay accuracy for the method is within 80-120% of the actual value. Intra- and inter-assay precision has a coefficient of variation less than 20%. The lower limit of quantification of the method is 0.2 nM with 100 ul plasma (absolute amount of 20 pmol analyte). Results of this assay applied to the analysis of plasma samples in pharmacokinetic and pharmacodynamic studies supporting intermittent dosing will be presented.