tbuckley/cabot-search huggingface dataset:
Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas
Authors: Audrey Bouillez, Hasan Rajabi, Sean Pitroda, Caining Jin, Maroof Alam, Akriti Kharbanda, Ashujit Tagde, Kwok-Kin Wong, Donald Kufe
Journal: Cancer Research (2016)

Dysregulation of MYC expression is a hallmark of cancer, but the development of agents that target MYC has remained challenging. The oncogenic MUC1-C transmembrane protein is, like MYC, aberrantly expressed in diverse human cancers. The present studies demonstrate that MUC1-C induces MYC expression in KRAS mutant non-small cell lung cancer (NSCLC) cells, an effect that can be suppressed by targeting MUC1-C via shRNA silencing, CRISPR editing, or pharmacologic inhibition with GO-203. MUC1-C activated the WNT/β-catenin (CTNNB1) pathway and promoted occupancy of MUC1-C/β-catenin/TCF4 complexes on the MYC promoter. MUC1-C also promoted the recruitment of the p300 histone acetylase (EP300) and, in turn, induced histone H3 acetylation and activation of MYC gene transcription. We also show that targeting MUC1-C decreased the expression of key MYC target genes essential for the growth and survival of NSCLC cells, such as TERT and CDK4. Based on these results, we found that the combination of GO-203 and the BET bromodomain inhibitor JQ1, which targets MYC transcription, synergistically suppressed MYC expression and cell survival in vitro as well as tumor xenograft growth. Furthermore, MUC1 expression significantly correlated with that of MYC and its target genes in human KRAS mutant NSCLC tumors. Taken together, these findings suggest a therapeutic approach for targeting MYC-dependent cancers and provide the framework for the ongoing clinical studies addressing the efficacy of MUC1-C inhibition in solid tumors.
Phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of BCG-refractory non-muscle-invasive bladder cancer.
Authors: L. J. Barlow, M. A. Laudano, M. J. Mann, M. Desai, D. P. Petrylak, M. C. Benson, J. M. McKiernan
Journal: Journal of Clinical Oncology (2010)

4542 Background: Up to 50% of patients treated with intravesical agents for non-muscle-invasive bladder cancer will recur. Response rates to current second line intravesical therapies average less than 20%. For these high risk patients, novel agents are necessary. Our previous phase I trial showed docetaxel to be a safe and efficacious agent for intravesical therapy. Nanoparticle albumin-bound (nab-)paclitaxel has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy and was therefore deemed an appropriate candidate for further investigation as an intravesical agent. Methods: This phase I trial began enrollment on 1/1/08, and the primary endpoint was reached as of 1/1/10. Inclusion criteria included recurrent high grade (HG) Ta, T1 and Tis transitional cell carcinoma failing at least one prior regimen of BCG. 6 weekly instillations of nab-paclitaxel were administered beginning at a dose of 150 mg at a concentration of 5mg/ml in normal saline with a dose escalation model used until a maximal deliverable dose (MDD) of 500 mg/100ml was achieved. The primary endpoints were dose-limiting toxicity (NCI common toxicity criteria grade 3 or 4 toxicity) and MDD; the secondary endpoint was response rate. Efficacy was evaluated by cystoscopy with biopsy, cytology, and CT imaging. Results: 18 patients were enrolled and received dose levels of 150, 225, 300, 375, 450, and 500 mg. One patient demonstrated measurable systemic absorption of nab-paclitaxel at the 450 mg dose as measured by HPLC assays (16.8 ng/mL; median detected level after standard intravenous administration: 18,000 ng/mL). 56% (10/18) of patients experienced grade 1 local toxicities, with dysuria being the most common. No grade 2, 3 or 4 drug related local toxicities have been encountered. 28% (5/18) of patients had no evidence of disease at their post-treatment cystoscopy. One patient had disease progression at the time of recurrence. Conclusions: Intravesical nab-paclitaxel exhibited minimal toxicity and systemic absorption in the first ever human intravesical dose escalation trial. A larger phase II prospective clinical trial at the 500mg dose level has been initiated. No significant financial relationships to disclose.
Tryptophanase of Fecal Flora as a Possible Factor in the Etiology of Colon Cancer23
Authors: King-Thom Chung, George E. Fulk, Milton W. Slein
Journal: JNCI Journal of the National Cancer Institute (1975)

Journal Article Tryptophanase of Fecal Flora as a Possible Factor in the Etiology of Colon Cancer Get access King-Thom Chung, King-Thom Chung Search for other works by this author on: Oxford Academic PubMed Google Scholar George E. Fulk, George E. Fulk Search for other works by this author on: Oxford Academic PubMed Google Scholar Milton W. Slein Milton W. Slein Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 54, Issue 5, May 1975, Pages 1073–1078, https://doi.org/10.1093/jnci/54.5.1073 Published: 01 May 1975 Article history Received: 05 August 1974 Accepted: 14 January 1975 Published: 01 May 1975
Minding our words
Authors: Kamran Abbasi
Journal: BMJ (2016)

We must choose our words carefully. Take Jeremy Hunt, for example. England’s health secretary has earned a reputation for misrepresenting statistics on weekend mortality and exaggerating the effects of industrial action by doctors (doi:10.1136/bmj.h6358). Mindful of Hunt’s scare tactics about the effects of reduced staffing, you might be surprised to learn that the NHS did not collapse after the junior doctors’ strike on 12 January (doi:10.1136/bmj.i314).

As rational thinkers, we will withhold judgement on the effect of the strike on outcomes …
Survivin silencing sensitizes imatinib-resistant CML cells to the cytotoxic effect of hydroxyurea
Authors: F. Stagno, E. Conte, S. Stella, E. Tirrò, L. Manzella, E. Palio, R. Giustolisi, A. Messina, P. Vigneri
Journal: Journal of Clinical Oncology (2006)

13119 Background: Imatinib Mesylate (IM), a semi-specific inhibitor of the BCR-ABL tyrosine kinase, is currently the treatment of choice for Chronic Myeloid Leukemia (CML). However, about one third of CML patients treated with IM develop resistance to the drug because of reactivation of BCR-ABL kinase activity. This phenomenon is usually ascribed to the amplification of the BCR-ABL gene or to the selection of leukemic clones harboring point mutations that abrogate IM binding. To identify novel anti-apoptotic signaling pathways employed by BCR-ABL and devise strategies capable of killing IM-resistant CML cells, we investigated the interplay between BCR-ABL and the Inhibitor of Apoptosis Protein Survivin. Methods: Murine hematopoietic cells (32D) transduced with p210 BCR-ABL and human cell lines either positive (K562, KCL22, KYO1 and LAMA84) or negative (HL60) for the BCR-ABL oncoprotein, were analyzed for Survivin expression by western blot before and after IM treatment. Three different pathways (MAPK, PI3K and JAK2/STA3) potentially involved in BCR-ABL-mediated induction of Survivin were studied using inhibitors specific for each signaling cascade. The effect of Survivin on the proliferation and viability of IM-sensitive and IM-resistant CML cells was investigated after silencing Survivin expression with small interfering RNAs. Results: BCR-ABL tyrosine kinase activity induced an over-expression of Survivin in both human and murine hematopoietic cell lines. This over-expression was both at the transcriptional and the translational level and required the JAK2/STAT3 pathway. Survivin silencing by siRNA increased IM cytotoxicity in IM-sensitive cells but failed to restore IM efficacy in IM-resistant cells. However, Survivin silencing sensitized CML cells to the cytotoxic effect of hydroxyurea and enhanced the efficacy of this compound on three different murine cell lines are insensitive to IM because of point mutations in the BCR-ABL kinase domain (Ba/F3p210Y253F, Ba/F3p210D276G and Ba/F3p210T315I). Conclusions: Reduction of Survivin expression improves the efficacy of IM and increases the sensitivity of IM-resistant CML cells to hydroxyurea. Survivin may represent an attractive therapeutic target for both IM-sensitive and IM-resistant CML patients. No significant financial relationships to disclose.
Potency of endotoxin from bicarbonate dialysate compared with endotoxins from Escherichia coli and Shigella flexneri.
Authors: L A Bland, J C Oliver, M J Arduino, C W Oettinger, S K McAllister, M S Favero
Journal: Journal of the American Society of Nephrology (1995)

Endotoxin is a potent activator of the complement system and other host immunoregulators, including the cytokines, tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6. In this study, the potency of an endotoxin from bicarbonate dialysate was compared with endotoxins from two enteric microorganisms, Shigella flexneri and Escherichia coli. Endotoxin concentrations were standardized for the three endotoxins by use of the Limulus amebocyte lysate turbidimetric assay. Endotoxin potency was assessed by the comparative plasma concentrations of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 after an in vitro whole-blood challenge by each type of endotoxin. Blood collected from 10 hemodialysis patients was spiked with 0.1, 1, and 10 ng/mL of E. coli and Shigella endotoxin and with 1 and 10 ng/mL of bicarbonate dialysate endotoxin. After incubation, plasma was separated and frozen at -70 degrees C until assayed for cytokine concentrations. Dialysate endotoxin was found to be 10 to 100 times less potent than E. coli and Shigella endotoxins. It was concluded that there are significant differences in the potency of endotoxins from different strains of bacteria and that these differences should be noted when designing or evaluating studies on the clinical effects of endotoxins in hemodialysis settings.
Co-morbid conditions associated with tuberculosis (TB): Results from a 1-day, point-prevalence study in 204,912 physician diagnosed patients from 880 cities and towns in India
Authors: Komalkirti Apte, Monica Barne, Sapna Madas, Jaideep Gogtay, Sushmeeta Chhowwala, Nadar Maharajan, Sundeep Salvi
Journal: European Respiratory Journal (2013)

Introduction: Tuberculosis is known to be associated with several co-morbid conditions such as human immunodeficiency virus (HIV) infections, diabetes and obstructive airway diseases (OADs). Aim: We aimed to study the association between physician diagnosed TB and co-morbid conditions in a large cross-sectional cohort in India. Methodology: 13,225 general practitioners, general physicians and pediatricians from 880 cities and towns were randomly selected and invited to participate in a 1-day point-prevalence study. On the study day all participating doctors captured details of age, gender, presenting symptoms and diagnosis of all patients who visited them. Clean data was transferred into the Epi Info software and associations between Tuberculosis and other co-morbid conditions were analyzed using chi-square test. Results: 7,400 doctors consented and provided clean data of 204,912 patients (M:54%; F:46%). Out of these, 3719 (1.8%) patients were reported to have TB (M:F 59.8%:40.2%, mean age: 35.7 ± 19.7 yrs). Patients diagnosed with TB showed a strong association with anemia [OR: 2.2 (1.9, 2.4); p
Erdosteine oral treatment of hospitalised COPD exacerbation prolongs time to first re-exacerbation
Authors: Maurizio Moretti
Journal: European Respiratory Journal (2014)

Introduction  Patients hospitalised for acute exacerbation of COPD (AECOPD) are at high-risk for recurrence within 8 weeks after the initial exacerbation.  Objective  This study evaluated the effect of erdosteine, an anti-oxidant mucolytic agent with antiadhesive bacterial properties, given to hospitalised AECOPD patients on the prevention of exacerbation.  Methods  Forty hospitalised COPD patients randomly received erdosteine (E) 900 mg daily or placebo (P) for 10 days plus standard treatment. Timing of first exacerbation after hospital discharge was assessed at 30 and 60 days. Data were correlated to FEV 1 %pred and serum C-reactive protein (CRP) measured at 10 and 30 days after hospitalisation.  Time-to-event analyses were performed with the use of the log-rank test; Cox regression analysis was used to estimate hazard ratios with 95% CI for three predictors of re-exacerbations, adjusted for each other.  Results  Re-exacerbations occurred in 25% of patients. (E) was associated with a faster decrease of CRP concentration (p  Conclusions  Erdosteine given to hospitalised patients with AECOPD shows a protective effect by delaying and reducing re-exacerbations.
Abstract 19925: Isolated Diastolic Hypotension is a Risk Factor for Incident Heart Failure in Community-Dwelling Older Adults with Wide Pulse Pressure
Authors: Jason Guichard, Ravi V Desai, Mustafa I Ahmed, Marjan Mujib, Susan J Zieman, Michel White, Wilbert S Aronow, Gregg C Fonarow, Ali Ahmed
Journal: Circulation (2010)

Background: We have previously demonstrated that isolated diastolic hypotension is common in older adults and is associated with increased risk of heart failure (HF). However, it is not clear if th...
HER2 status of gastric and gastroesophageal cancer (GC) patients assessed by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and high-resolution array comparative genomic hybridization (aCGH).
Authors: Y. Y. Janjigian, V. V. Barbashina, D. P. Kelsen, L. H. Tang, D. Ilson, L. J. Tafe, J. B. Hicks, M. A. Shah
Journal: Journal of Clinical Oncology (2010)

4103 Background: The ToGA study established the benefit of trastuzumab in HER2-positive GC. Accurate HER2 molecular assessment is crucial for patient selection for trastuzumab therapy. It is estimated by the ASCO/CAP that ∼20% of HER2 breast cancer (BC) testing is inaccurate. aCGH is a reliable, sensitive, and high-resolution method that characterizes gene copy number alternations present in tumors. aCGH is increasingly used as a research tool to help identify HER2-positive BC patients. Potential heterogeneity of HER2 amplification and incomplete membrane staining of HER2 by IHC leaves ambiguity of HER2 positivity in GC. We examined HER2 status by IHC, FISH, and aCGH in MSKCC GC patients with the aim to better define HER2-positive GC. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor specimens of patients with GC were HER2 tested by FISH (PathVysion, Abbott-Vysis) and IHC (4B5, Ventana) at MSKCC and aCGH on Agilent 244K feature arrays at Cold Spring Harbor Laboratory. IHC and FISH results were scored according to the ASCO/CAP guidelines for BC. Age, gender, histology, stage, therapy, and survival were also recorded. Results: 100 patients with advanced GC have been studied. 22 women, 78 men. Median age 59. Median survival is 14 months, independent of HER2 status. aCGH analysis is ongoing; results are available on 22 patients (14 FISH positive, 5 FISH negative, 3 FISH equivocal), of which 1 IHC3+/FISH+ pt was found to be HER2 negative by aCGH. Conclusions: 21% of GC are HER2 FISH positive. FISH concordance rate is 100% for IHC positive and 94% for IHC negative. aCGH analysis is feasible on FFPE GC tumor specimens. We note a 93% concordance rate between FISH and aCGH positivity in GC thus far; additional analysis is ongoing. N=100 IHC0-1+ negative IHC2+equivocal IHC3+positive aCGH positive* log2 ratio >1.3 aCGH negative* Total FISH Positive >2.2 HER2:CEP17 1 3 16** 13 1 21* Negative <1.8 HER2:CEP17 66 3 0 5 71 Equivocal 1.8-2.2 HER2:CEP17 3 1 0 3 4 * Analysis is ongoing. ** 1 pt FISH+/IHC not available, 1 pt IHC 3+/FISH test failure. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GenDx, Inc. GenDX, Inc.
Précision diagnostique du zoom optique endoscopique avec narrow-band imaging renforcé par l’acide acétique dans les cancers gastriques superficiels
Authors: G. Rahmi
Journal: Endoscopy (2015)

L’exploration endoscopique optimale de la surface muqueuse au niveau de l’estomac est indispensable au dépistage des lésions pré-néoplasiques ou néoplasiques et à leur traitement. Cette exploration est devenue de plus en plus précise, d’une part grâce à une image endoscopique haute définition en lumière blanche (WLE), et d’autre part grâce à la coloration virtuelle par NBI (narrow-band imaging) avec zoom optique (NBIME) couplée ou non à l’acide acétique 1,5 % (A-NBIME).
CDK2 and CDK1 specific activities: A novel prognostic indicator in early breast cancer
Authors: S. Kim, N. Masuda, H. Inaji, K. Yoshidome, M. Tsujimoto, F. Akiyama, H. Ishihara, G. N. Hortobagyi, N. T. Ueno, S. Noguchi
Journal: Journal of Clinical Oncology (2007)

10592 Background: Cyclin-dependent kinases (CDKs) are expressed almost constantly but their activities change according to cell cycle phase. We studied the specific activity (SA; activity/expression) of CDKs to accurately evaluate their role in cell proliferation. We focused on the ratio of CDK2 SA to CDK1 SA because this ratio has been associated with rapid tumor growth in human breast cancer xenografts. Our goal was to investigate the prognostic significance of CDK2/1 ratio in node-negative breast cancer. Methods: We used a novel assay to measure SAs of CDK2 and CDK1 in 365 primary breast tumors. All tumors were histologically confirmed invasive breast cancer without lymph node involvement. The primary endpoint was relapse-free survival (RFS). Cut-off values for CDK2/1 ratio were defined as those points that best discriminated groups according to RFS. Tumors were grouped as low (136pts), intermediate (84pts), and high (145pts) CDK2/1 ratio. The median follow-up was 59 months (range 4–102). Results: Pts characteristics are described as follows: menopausal status: pre- 42%, post- 58%; tumor size: =20mm 48%, &gt;20mm 52%; histologic grade (HG): I 28%, II 47%, III 23%; ER: (+) 57%, (-) 42%; PR: (+) 51%, (-) 48%. Pts with HG III or high CDK2/1 ratio showed significantly lower 5y-RFS rates than those with HG I/II or low/intermediate CDK2/1 ratio, respectively (HG: I 97%, II 91%, III 85%, P=0.040; CDK2/1 ratio: low 97%, intermediate 92%, high 85%, P=0.017). In univariate analysis, PR (- vs +, P=0.088) had a tendency to associate with relapse, and HG (III vs I, P=0.024) and CDK2/1 ratio (high vs low, P=0.011) also had a significant correlation with relapse. However, only CDK2/1 ratio showed a significant independent prognostic indicator in multivariate analysis (hazard ratio 2.86, 95% CI 1.25–6.58, P=0.01). More important, among women (n=185) with hormone receptor (HR) positive disease given adjuvant hormone therapy alone, who have had no useful factors to predict their outcomes, high CDK2/1 ratio was also associated with worse prognosis than low CDK2/1 ratio (5y-RFS 84% vs 100%, P=0.007). Conclusions: For patients with node- negative disease, especially those with HR positive tumors given adjuvant hormone therapy alone, the CDK2/1 ratio might be useful as a routine laboratory test to predict outcome. No significant financial relationships to disclose.
Abstract 18382: Rna Splicing Regulated by A2bp1 is Essential for Cardiac Function in Zebrafish
Authors: Karen S Frese, Benjamin Meder, Andreas Keller, Jan Haas, Steffen Just, Hugo A Katus, Wolfgang Rottbauer
Journal: Circulation (2014)

Objective: Alternative splicing (AS) is one of the key mechanisms for the proteomic and functional diversity of eukaryotes. However, the complex nature of AS, its associated regulators and their targets are only partially understood. In the present study we investigated the transcriptomic diversity in the zebrafish heart using RNA-Sequencing and elucidated the functional role of the splicing regulator A2BP1 in vivo. Results: Using RNA-Sequencing we characterized the cardiac transcriptome of 48 hours post fertilization (hpf) old zebrafish embryos and compared the expression of genes and their isoforms to whole fish tissue. Besides the known cardiac genes, we found several previously described genes, highly expressed in cardiac tissue. The analysis of RNA-Seq data indicates that 14% of all genes expressed in the heart undergo AS by single exon-skipping/inclusion. To determine the effect of splicing factors on mRNA splicing we investigated the functional role of splicing regulator a2bp1 in vivo by using the zebrafish as a model organism. Morpholino-mediated a2bp1 knockdown in zebrafish embryos led to progressive cardiac contractile dysfunction, suggesting an important role of a2bp1 in maintenance of cardiac function. Splicing analysis revealed that loss of a2bp1 does not result in a completely splicing failure, but rather alters the splicing pattern of specific target genes. Here we identified novel spliceforms and potentialy novel targets of splicing factor a2bp1. Splice-junction blockage experiments showed that a balanced isoform expression of the targets actn3a, hug, ktn1, ptpla and camk2g is necessary for maintaining cardiac function in zebrafish. We assume, that the a2bp1-knockdown phenotype is not caused by missplicing of specific targets rather by the cumulative effect of many splicing abnormalities. Conclusion: Our study reveal a novel splicing regulator that is necessary for normal heart function. We showed that dysfunction of a2bp1 not only leads to heart failure, but show that a2bp1 mediates the splicing of different transcripts which might mediate the observed phenotype. Our results highlight the importance of balanced mRNA splicing in the heart and represents intriguing opportunities for novel therapeutic approaches.
Vascular Dissemination of Tumor Cells in Relation to Temperature-Dependent Metastasis in Frogs&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Sergio F. Juacaba, Robert G. McKinnell, William J. Hanson, David Tarin
 6
Journal: JNCI Journal of the National Cancer Institute (1987)

Metastasis is a temperature-related phenomenon in the North American leopard frog (Rana pipiens) affected with the Lucké renal adenocarcinoma. The frog is a poikilothermic vertebrate whose internal body temperature closely follows that of the environment, and tumor-bearing frogs living in a warm (28 degrees C) environment have a much higher incidence of metastasis (greater than 75%) than those in cold (4 degrees C) conditions (less than 6%). In this investigation it was found that Lucké tumor cells labeled with fluorescein isothiocyanate could be detected in frozen sections of all organs examined within 15 minutes, regardless of whether the hosts were adapted to a warm or a cold environment. Separate experiments involving inoculation of isotope-labeled tumor cells demonstrated that large numbers of cells arrived in the liver and other organs of animals kept at either end of the temperature range. These findings show that the infrequency of metastasis by Lucké adenocarcinomas in chilled frogs is not due to failure of dissemination of tumor cells consequent upon temperature-mediated changes in blood viscosity or flow patterns. Thus they establish the important baseline that the effects of temperature on metastasis in this vertebrate are exerted directly on the tumor cells and/or the internal environment of the host and that the system therefore provides new opportunities for probing the biology and biochemistry of tumor metastasis.
pH‐Responsive Fe(III)–Gallic Acid Nanoparticles for In Vivo Photoacoustic‐Imaging‐Guided Photothermal Therapy
Authors: Jianfeng Zeng, Ming Cheng, Yong Wang, Ling Wen, Ling Chen, Zhen Li, Yongyou Wu, Mingyuan Gao, Zhifang Chai
Journal: Advanced Healthcare Materials (2016)

pH-responsive biocompatible Fe(III)-gallic acid nanoparticles with strong near-infrared absorbance are very stable in mild acidic conditions, but easily decomposed in neutral conditions, which enables the nanoparticles to be stable in a tumor and easily metabolized in other organs, thus providing a safe nanoplatform for in vivo photoacoustic imaging/photothermal therapy theranostic applications.