tbuckley/cabot-search huggingface dataset:
Abstract 17012: Prognostic Value of Global and Regional Right Ventricular Strain and Dyssynchrony by Speckle Tracking Echocardiography in Acute Pulmonary Embolism: Comparison to Measures of RV function by Computed Tomography and Transthoracic Echocardiography
Authors: Nina Ghosh, Elizabeth George, Carlos Gonzalez Quesada, Kanako K Kumamaru, Nicole Wake, Arash Bedayat, John Groarke, Amir Imanzadeh, Sachin Saboo, Ruth Dunne, Judy Mangion, Andetta Hunsaker, Ashish Khandelwal, Frank J Rybicki, Marie Gerhard-Herman
Journal: Circulation (2013)

Background:  Right ventricular (RV) strain and RV dyssynchrony measured by speckle tracking echocardiography (SPE) are altered in acute pulmonary embolism (PE). The prognostic utility of these measures have not been compared to conventional echocardiographic and computed tomography (CT) measures of RV dysfunction. We sought to determine the relative prognostic value of RV strain compared to that of CT RV/LV diameter ratio and conventional measures of RV dysfunction by transthoracic echocardiography (TTE).   Hypothesis:  Global and regional RV strain by SPE will allow for improved risk stratification in acute PE.   Methods:  200 consecutive patients diagnosed with acute PE by CT pulmonary angiography who had a TTE within 48 hours were included. Global RV strain and regional RV strain in six segments (basal-, mid- and apical- free and septal walls, respectively) were measured using offline speckle tracking software. The standard deviation (SD) of the time to peak for the 6 segments was used to quantify RV dyssynchrony. The predictive ability (Area under the Curve; AUC) of the SPE measures of strain for PE-related mortality was compared to that of CT RV/LV ratio and TTE measures of RV dysfunction.   Results:  Mean longitudinal strain was -18 +/-7.9 in the overall cohort. Regional strain was greatest in the basal lateral segment (-22 +/-14.9) and lowest in the apical septal segment (16.7 +/- 9.2). RV dyssynchrony was 92.9+/-67. There were 13 PE-related deaths. The predictive value of mean longitudinal strain (AUC = 0.64), basal RV free wall strain (AUC = 0.64) and mid RV free wall strain (AUC = 0.70) were not significantly different than that of CT RV/LV ratio, TTE RV/LV ratio and PASP by TTE (AUC 0.61, 0.64, and 0.65, respectively). Mid free wall strain had significantly better predictive value than dyssynchrony (AUC = 0.43, p   Conclusion:  Patterns of global and regional RV longitudinal strain and dyssynchrony are described. Although we showed that global and mid free wall RV strain by SPE has similar prognostic ability for PE-related death compared to conventional measures of RV dysfunction by CT and TTE, larger studies are required to confirm these findings.
Abstract 13081: The Central Nervous System Regulates Inflammation and Cardiac Remodeling During Pressure Overload Through NLRP3 Inflammasome Activation
Authors: Yasutomi Higashikuni, Masataka Sata, Issei Komuro
Journal: Circulation (2014)

Background:  Interleukin-1β (IL-1β) has been shown to be upregulated in the heart during pressure overload through Toll-like receptor (TLR) signaling and contribute to cardiac remodeling. IL-1β requires the proteolysis of pro-IL-1β in generation of active form, and the NLRP3 inflammasome has been reported to play a pivotal role in this process by the catalytic activation of caspase-1. This study was performed to clarify the role and the mechanisms of the NLRP3 inflammasome activation in pressure overload-induced cardiac hypertrophy.   Methods and Results:  Pressure overload was induced in mice by transverse aortic constriction (TAC). In wild-type (WT) mice, NLRP3 was upregulated in the heart after TAC with increased caspase-1 activation and active IL-1β production, which were suppressed in  Nlrp3  knockout (KO) mice. At 2 weeks after TAC, KO mice showed reduced cardiac hypertrophy and fibrosis with more left ventricular dilatation and impaired systolic function compared with WT mice, indicating impaired cardiac adaptive response to pressure overload. In vitro experiments revealed that extracellular ATP, in combination with a specific ligand for TLR2, synergistically induces cardiomyocyte hypertrophy and proliferation of fibroblasts and vascular endothelial cells through NLRP3 inflammasome activation via the P2X7 receptor. Pharmacological inhibition of the P2X7 receptor or depletion of extracellular ATP in WT mice resulted in suppressed NLRP3 inflammasome activation and impaired adaptive cardiac hypertrophy after TAC. ATP is one of neurotransmitters released from the sympathetic nerve terminals. We found that sympathetic activation induces caspase-1 activation in WT hearts, whereas sympathetic inhibition by the left stellate ganglionectomy or clonidine suppressed NLRP3 inflammasome activation and impaired adaptive cardiac hypertrophy after TAC in WT mice. Besides, WT mice undergoing ablation of afferent nerves from the heart by capsaicin showed the same phenotype with those with sympathetic inhibition after TAC.   Conclusions:  Our results suggest that NLRP3 inflammasome activation is regulated by the central nervous system through the ATP/P2X7 signaling axis and contributes to adaptive cardiac hypertrophy during pressure overload.
Postive sentinel nodes after neoadjuvant chemotherapy: What factors predict additional disease in the axilla?
Authors: J. S. Jeruss, G. D. Ayers, M. Cristofanilli, M. I. Ross, G. Babiera, F. Meric-Bernstam, H. M. Kuerer, B. W. Feig, M. Yi, K. K. Hunt
Journal: Journal of Clinical Oncology (2006)

602 Background: The predictive utility of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy is similar to that for patients treated initially with surgery. We hypothesized that patients with positive SLNs after chemotherapy would have unique clinical and pathologic factors predictive of additional non-SLN positivity. Methods: From 1993 - 2005, 104 patients were identified from a prospective database who responded to neoadjuvant therapy, had a positive SLNB, and underwent axillary dissection. At presentation, 66 patients had clinically negative nodes (CN) by ultrasound, and 38 patients had positive nodes by fine needle aspirate (Pos). Univariate and multivariate assessments of 17 predictive factors for additional non-SLN disease were performed using chi-square and logistical regression analysis with a bootstrapped backwards elimination procedure. Results: Patients with CN nodes (47%) were less likely to have additional non-SLNs positive when compared to patients with FNA Pos nodes at presentation (71%) (p=0.017). In additional univariate analysis, method of SLN metastasis detection, lymphovascular invasion (LVI), multicentricity, LN response to neoadjuvant therapy, nuclear grade, number of SLNs positive, and size of SLN metastasis were predictive for additional positive non-SLNs (p ≤ 0.05). In multivariate analysis, LVI, method of SLN metastasis detection, multicentricity, axillary node status at presentation, and pathologic tumor size retained grouped significance with a bootstrap adjusted AUC of 0.762. A nomogram for predicting non-SLN metastasis was created incorporating these variables. Multifocality, ER, nuclear grade, and number of negative or positive SLNs did not add statistical predictive power to our model. Conclusions: Patients treated with neoadjuvant therapy who have positive SLNs are at high risk of having additional non-SLN disease; use of a nomogram may help to risk-stratify this patient population. We have identified unique predictive variables for these patients, including multicentricity and nodal status at presentation, that indicate additional non-SLN disease when the SLN is positive. We plan to validate the predictive ability of the multivariate results for this patient population prospectively. No significant financial relationships to disclose.
Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis
Authors: Fei Teng, Wen-Yan Tian, Ying-Mei Wang, Yan-Fang Zhang, Fei Guo, Jing Zhao, Chao Gao, Feng-Xia Xue
Journal: Journal of Hematology & Oncology (2016)

Cancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development. However, little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC) progression. We aim to detect the functional contributions of CAFs to promote progression of EC. Stromal fibroblasts were isolated from endometrioid adenocarcinomas and normal endometrial tissues. The conditioned media of cultured CAFs and normal fibroblasts (NFs) were collected to detect the level of stromal cell-derived factor-1alpha (SDF-1α), macrophage chemoattractant protein-1 (MCP-1), migration inhibitory factor (MIF), colony stimulating factor-1 (CSF-1), and interleukin-1 (IL-1) by ELISA. The CAFs or NFs were cocultured with EC cell lines to determine the proliferation, migration, and invasion by MTT assays and transwell chambers. Xenograft models were used to observe tumor growth. Matrix metalloproteinases (MMP)-2 and MMP-9 activity was evaluated by zymography. AMD3100 (a chemokine receptor 4 (CXCR4) antagonist) was used to block the SDF-1/CXCR4 axis. Neutralizing antibodies were used to detect PI3K/Akt and MAPK/Erk pathways by western blotting. SDF-1α and CXCR4 expressions were analyzed in xenotransplanted tumors and 348 cases by immunohistochemistry. CAFs promoted proliferation, migration, and invasion as well as in vivo tumorigenesis of admixed EC cells significantly more than NFs by secreting SDF-1α. These effects were significantly inhibited by AMD3100. CAFs promoted EC progression via the SDF-1α/CXCR4 axis to activate the PI3K/Akt and MAPK/Erk signalings in a paracrine-dependent manner or increase MMP-2 and MMP-9 secretion in an autocrine-dependent manner. SDF-1α and CXCR4 expression upregulation accompanied clinical EC development and progression. High SDF-1α expression levels were associated with deep myometrial invasion, lymph node metastasis, and poor prognosis in EC. Our data indicated that CAFs derived from EC tissues promoted EC progression via the SDF-1/CXCR4 axis in a paracrine- or autocrine-dependent manner. SDF-1α is a novel independent poor prognostic factor for EC patients' survival. Targeting the SDF-1/CXCR4 axis might provide a novel therapeutic strategy for EC treatment.
Cost-effectiveness of targeting chemotherapy with the 70-gene prognostic signature in early-stage breast cancer (ESBC) patients
Authors: K. B. Tong, E. Chen, G. Brink, R. Bender, F. de Snoo, J. Malin
Journal: Journal of Clinical Oncology (2009)

6570 Background: The 70-gene microarray test (MammaPrint) has been shown to provide additional prognostic information to clinicopathologic risk assessment for women ESBC; however, the cost-effectiveness of this strategy is not well understood. Methods: The objective of this analysis was to estimate the incremental benefits, costs, and cost-effectiveness of the treatments guided by the 70-gene signature versus Adjuvant! Software (AS) to decide on the use of adjuvant chemotherapy for women ≤61 years with lymph node negative, HER-2 negative ESBC with estrogen receptor (ER) positive or negative disease. A Markov model with a lifetime horizon and three health states (alive without recurrence, death from cancer and death from other causes) was constructed using TreeAge Pro software. Risk classification and patient outcomes data were based on a multi-center 70-gene signature validation study. Efficacy of chemotherapy derived from published meta-analysis of clinical trials. Costs and health utilities were obtained from the literature. Costs and benefits were discounted 3%/year. Results: Compared to AS, the 70-gene signature strategy resulted in 35% of patients being reassigned to a different risk classification and avoided chemotherapy in 9% of patients. In the base case, the 70-gene signature strategy was cost neutral (lifetime costs per patient: $178,811 versus $178,893 for the 70-gene signature and AS strategy). Moreover the 70-gene signature strategy was associated with an increase of 0.13 life years (LYs) and 0.16 quality adjusted life years (QALYs). The model results were sensitive to the cost of 70-gene signature test, cost of adjuvant chemotherapy, and relative risk reduction associated with chemotherapy; however, the 70-gene strategy remained cost-effective across a wide range of assumptions. Conclusions: In this analysis, the 70-gene signature was associated with a reduction in chemotherapy use and an increase in life expectancy. The 70-gene signature appears to be a cost-effective strategy for obtaining additional information to guide the decision to use adjuvant chemotherapy in patients with lymph node negative ESBC. [Table: see text]
Nomograms to Predict Recurrence-Free and Overall Survival After Curative Resection of Adrenocortical Carcinoma
Authors: Yuhree Kim, Georgios A. Margonis, Jason D. Prescott, Thuy B. Tran, Lauren M. Postlewait, Shishir K. Maithel, Tracy S. Wang, Douglas B. Evans, Ioannis Hatzaras, Rivfka Shenoy, John E. Phay, Kara Keplinger, Ryan C. Fields, Linda X. Jin, Sharon M. Weber, Ahmed I. Salem, Jason K. Sicklick, Shady Gad, Adam C. Yopp, John C. Mansour, Quan-Yang Duh, Natalie Seiser, Carmen C. Solorzano, Colleen M. Kiernan, Konstantinos I. Votanopoulos, Edward A. Levine, George A. Poultsides, Timothy M. Pawlik
Journal: JAMA Surgery (2015)

Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine tumor, and the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined.To define clinicopathological variables associated with recurrence-free survival (RFS) and overall survival (OS) after curative surgical resection of ACC and to propose nomograms for individual risk prediction.Nomograms to predict RFS and OS after surgical resection of ACC were proposed using a multi-institutional cohort of patients who underwent curative-intent surgery for ACC at 13 major institutions in the United States between March 17, 1994, and December 22, 2014. The dates of our study analysis were April 15, 2015, to May 12, 2015.The discriminative ability and calibration of the nomograms to predict RFS and OS were tested using C statistics, calibration plots, and Kaplan-Meier curves.In total, 148 patients who underwent surgery for ACC were included in the study. The median patient age was 53 years, and 65.5% (97 of 148) of the patients were female. One-third of the patients (35.1% [52 of 148]) had a functional tumor, and the median tumor size was 11.2 cm. Most patients (77.7% [115 of 148]) underwent R0 resection, and 8.8% (13 of 148) of the patients had N1 disease. Using backward stepwise selection of clinically important variables with the Akaike information criterion, the following variables were incorporated in the prediction of RFS: tumor size of at least 12 cm (hazard ratio [HR], 3.00; 95% CI, 1.63-5.70; P < .001), positive nodal status (HR, 4.78; 95% CI, 1.47-15.50; P = .01), stage III/IV (HR, 1.80; 95% CI, 0.95-3.39; P = .07), cortisol-secreting tumor (HR, 2.38; 95% CI, 1.27-4.48; P = .01), and capsular invasion (HR, 1.96; 95% CI, 1.02-3.74; P = .04). Factors selected as predicting OS were tumor size of at least 12 cm (HR, 1.78; 95% CI, 1.00-3.17; P = .05), positive nodal status (HR, 5.89; 95% CI, 2.05-16.87; P = .001), and R1 margin (HR, 2.83; 95% CI, 1.51-5.30; P = .001). The discriminative ability and calibration of the nomograms revealed good predictive ability as indicated by the C statistics (0.74 for RFS and 0.70 for OS).Independent predictors of survival and recurrence risk after curative-intent surgery for ACC were selected to create nomograms predicting RFS and OS. The nomograms were able to stratify patients into prognostic groups and performed well on internal validation.
Community-acquired pneumonia during the influenza pandemic A(H1N1)pdm09 and post-pandemic period in hospitalized patients, Russia
Authors: Zinaida Bobyleva, Igor Leshchenko, Natalia Ponamareva, Yulia Morozova, Alexandra Plotnicova
Journal: European Respiratory Journal (2012)

Aim : The authors wondered whether the clinical characteristics have changed, comorbidities, radiological data, frequency admitted to the ICU, and outcomes in-patients with CAP in the post-pandemic period compared with the influenza pandemic period.   Methods:  This was a retrospective study including adults patients with CAP admitted to the Regional Hospital 1 during an pandemic A(H1N1)pdm09 between November 1, 2009 and January 15, 2010 (group A) and post-pandemic period between January 1 and April 20, 2011 (group B). Group A: 94 patients, mean age 36 ± 13 (men, 39%). Group B: 109 patients, mean age 43 ± 15 (men, 45%).  Results:  Patients with laboratory confirmed influenza A(H1N1)pdm09 (gr. A) 45% vs (gr. B) 28% (p. 0.02). In gr. B compared with gr. A: were hospitalized less often pregnant (30% vs 58%, p. 0.003), decreased the proportion of obese patients (14% vs 25 %, p. 0.05), less lung injury: 2-way process (55% vs 82%, p. 0.000) and loss of 2 or more segments (69% vs 80%, p. 0.000) and rarely detected «glass matte» (2% vs 11%, p. 0.03). In gr. B decreased need for admitted in the ICU (40% vs 62%, p. 0.002), with a smaller proportion of them are pregnant (9% vs 49%, p. 0.01). The length of stay in the ICU, the need for mechanical ventilation and the patients with laboratory confirmed A(H1N1)pdm09 not significantly different. The frequency of deaths in the groups did not differ significantly and was 18% (gr. B) vs 21% (gr. A).  Conclusion:  Among in-patients with CAP in post-pandemic period decreased: the number of persons infected with the virus A(H1N1)pdm09, the need for admitted in the ICU with a tendency to reduce the incidence of CAP in pregnant.
Antiestrogenic Action of 3-Hydroxytamoxifen in the Human Breast Cancer Cell Line MCF-7&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: W Roos, L Oeze, R Löser, U Eppenberger
Journal: JNCI Journal of the National Cancer Institute (1983)

The antiestrogenic action of 3-hydroxytamoxifen [trans-1-(4-beta-dimethylaminoethoxyphenyl)-1-(3-hydroxyphenyl)-2 -phenylbut-1-ene] was characterized in vitro and compared with that of tamoxifen [trans-1-(4-beta-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene]. The relative binding affinities of 3-hydroxytamoxifen to estrogen receptor were 3.3% in cytosol of MCF-7 cells and 1.5% in human mammary carcinoma cytosol compared to values of 0.2 and 0.3% for tamoxifen (the affinity of 17 beta-estradiol considered to be 100%). The concentration of 3-hydroxytamoxifen necessary to suppress the 17 beta-estradiol-induced growth stimulation of MCF-7 cells was about tenfold lower than that for tamoxifen. The induction of progesterone receptor in MCF-7 cells by 17 beta-estradiol was inhibited by 3-hydroxytamoxifen. In the absence of 17 beta-estradiol, 3-hydroxytamoxifen gave rise to a moderate increase in the progesterone receptor levels, which demonstrates the partially estrogenic character of hydroxytamoxifen.
Rabbit globin pseudogene psi beta 2 is a hybrid of delta- and beta-globin gene sequences.
Authors: R C Hardison, J B Margot
Journal: Molecular Biology and Evolution (1984)

The evolutionary history of the rabbit globin pseudogene psi beta 2 was studied by completing its nucleotide sequence and aligning the sequence with that of the rabbit adult globin gene beta 1 and the human minor adult globin gene delta. The 5' flanking region and exon 1 of psi beta 2 were most similar to rabbit beta 1, but the large intervening sequence and the 3' untranslated region were most similar to human delta. Intron 1 and exon 2 were equally similar to both delta and beta 1. This pattern indicates that psi beta 2 was originally a delta-like gene that acquired the 5' portion of gene beta 1 by intrachromosomal gene conversion. The presence of a delta-globin gene sequence in both rabbits and humans shows that it is an ancient gene, predating the mammalian radiation that occurred over 85 Myr ago. Delta has shown a pronounced tendency to be altered in its 5' end during the course of mammalian evolution. Quantitative divergence analysis shows that the ancestor to rabbit psi beta 2 was active until 20-30 Myr ago, during which time the lagomorph beta-globin gene family apparently functioned without a pseudogene.
Plasma human papillomavirus (HPV) DNA as a potential tool for tumor detection and monitoring response in HPV-related oropharyngeal carcinoma (OP).
Authors: H. Cao, S. Kwok, X. Shi, R. Bala, B. Pinsky, A. D. Colevas, N. Pourmand, A. Koong, C. Kong, Q. Le
Journal: Journal of Clinical Oncology (2010)

5529 Background: There is a rising incidence of HPV-related OP, which has a distinct prognosis. Previous studies in other viral-related cancers such as nasopharyngeal carcinoma have shown that the level of circulating instigating virus DNA in the blood can be used to monitor treatment response and tumor relapse. The main objective of this study is to develop a similar assay for HPV(+) OP. Methods: We designed a semiquantitative PCR approach to detect circulating HPV DNA using the L1 Gp5/6 degenerate primer as well as HPV16/18 E6 and E7 nested primers. We used this approach to detect HPV DNA in culture media of SCC90, a HPV(+) OP cell line as well as plasma samples of SCC90 bearing SCID mice. Control mice were those implanted with non-HPV tumors. HPV DNA was also assessed in pretreatment plasma samples of 32 HPV(+) OP patients and 4 HPV(-) control patients with other head and neck squamous cell carcinoma. HPV status within the tumor was confirmed by both p16 staining and HPV16/18 PCR (N = 30) or in-situ hybridization (n = 2). Plasma HPV DNA levels were also quantified by a fluorescent probe multiplex real-time PCR (QRTPCR) assay, targeting the HPV16/18 E6 region, in 6 patients with HPV(+) OP and serial plasma samples obtained during radiotherapy (RT). Results: Cell-free HPV DNA was detected in the culture media of SCC90 and the plasma of SCC90 bearing mice but not in control mice. It was detected in pretreatment plasma of 84% HPV(+) patients and in none of the HPV(-) controls using the L1 primers and conventional PCR. However using less sensitive primer sets (nested E6 and E7), plasma HPV DNA was positive in only 50% of patients with detectable E6/E7 DNA in the tumors. QRTPCR was able to detect as low as 10 copies of HPV DNA in each reaction. In 6 patients with serial plasma samples during RT, QRTPCR measurement showed a rapid decline in HPV DNA level, which became undetectable at RT completion. Conclusions: The xenograft studies indicate that plasma HPV DNA is released directly from HPV-related tumors. The high sensitivity of this method allows detection of HPV DNA in plasma even with low viral load. Plasma HPV DNA may be a valuable tool for monitoring therapeutic response and disease progression in HPV(+) OP. No significant financial relationships to disclose.
INDOLE DERIVATIVES OF PINEAL AND RELATED NEURAL AND RETINAL TISSUES
Authors: W.B. QUAY
Journal: Pharmacological Reviews (1965)

Resurgence of interest in the mammalian pineal organ and recemit successful experimental linkimig of its activity with the sympathetic system and environmental lighting, have been brought about in part by the pineal's content and metabolism of 5-hydroxy- and 5-methoxyindoles. Methods are being applied for exacting precise informatiomi concerning localization and quantification of these compounds and their derivatives within pineal tissue. Much remains to be learned, however, concerning the identity of postulated and unknown, metabolically active pineal indoles and their derivatives. Predilection, perhaps premature, for the hormonal possibilities of these derivatives has led to a neglect of the possibilities of strictly intramural or intrapineal functions for these compounds. The latter seem most promising in the light of recent uhtrastructural, histochemical, biochemical and comparative studies. The likelihood of a basic, primitive similarity between pineal, brain amid retinal tissue in their metabolites and metabolism of 5-hydroxyindoles also deserves study.