tbuckley/cabot-search huggingface dataset:
Effect of histone deacetylase inhibitor (HDACI) PCI-24781 on chemotherapy-induced apoptosis in multidrug-resistant sarcoma cell lines.
Authors: E. Choy, Y. Cao, F. Hornicek, K. B. Wood, J. H. Schwab, X. Liu, H. Mankin, Z. Duan
Journal: Journal of Clinical Oncology (2010)

10089 Background: The antitumor activity of histone deacetylase inhibitors (HDACI) on multidrug-resistant sarcoma cell lines has never been previously described. Methods: We treated chemotherapy-resistant osteosarcoma and chondrosarcoma cell lines with PCI-24781 in combination with chemotherapeutic agents. MTT assay was used to measure relative inhibition of cell growth in each of the conditions. Western blot analysis was used to determine changes in RAD51 and GADD45α levels as a result of treatment with PCI-24781. Caspase activity was measured with the Apo-One Homogeneous Caspase 3/7 assay kit (Promega Corporation). Results: Four multidrug-resistant sarcoma cell lines treated with HDACI PCI-24781 resulted in dose-dependent accumulation of acetylated histones, p21 and PARP cleavage products. Growth of these cell lines was inhibited by single agent PCI-24781 at IC50 of 0.43 to 2.7 μM. When we looked for synergy of PCI-24781 with chemotherapeutic agents, we found that PCI-24781 reverses drug resistance in all four multidrug resistant sarcoma cell lines and synergizes with chemotherapeutic agents to enhance caspase-3/7 activity. Expression of RAD51 (a marker for DNA double-strand break repair) was inhibited and the expression of GADD45α (a marker for growth arrest and DNA-damage) was induced by PCI-24781 in multidrug resistant sarcoma cell lines. Conclusions: HDACI PCI-24781 synergizes with chemotherapeutic drugs to induce apoptosis and reverses drug resistance in multidrug-resistant sarcoma cell lines. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacyclics
Biological Motion Perception, Brain Responses, and Schizotypal Personality Disorder
Authors: Ji-Won Hur, Randolph Blake, Kang Ik K. Cho, Jejoong Kim, So-Yeon Kim, Soo-Hee Choi, Do-Hyung Kang, Jun Soo Kwon
Journal: JAMA Psychiatry (2016)

Exploration of the ability to process socially relevant events portrayed by biological motion and to identify underlying neuronal processes can provide clues for understanding the pathophysiology of psychosis. Individuals with schizotypal personality disorder (SPD) have pervasive interpersonal deficits and odd behaviors. An understanding of the neural mechanisms involved in the perception of biological motion and the relation of activity to clinical symptoms in those mechanisms is needed.To investigate the specificity of brain regions responsive to biological motion perception in individuals with SPD compared with healthy control individuals.Twenty-one patients diagnosed as having SPD and 38 age-, sex-, and IQ-matched controls underwent event-related functional magnetic resonance imaging. The SPD group completed the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Schizotypal Personality Questionnaire for assessment of symptom severity. During scanning, all participants were required to discriminate biological from scrambled sequences of point-light animations. Data were collected from September 21. 2011, to July 13, 2013, and analyzed from March to May 2015.Blood oxygenation level-dependent signals during event-related scanning and symptom severity in the SPD group.The 21 individuals with SPD (16 men and 5 women) and 38 controls (29 men and 9 women) had a mean (SD) age, 22.8 (3.8) vs 22.2 (2.5) years and a mean (SD) IQ, 115.00 (12.55) vs 120.24 )7.68). Brain imaging revealed the presence of neuronal activation specific to biological motion within the posterior superior temporal sulcus. However, the individuals with SPD exhibited regions of neural responsiveness within brain regions forming the reward network, which consisted of the dorsal striatum and bilateral superior medial frontal cortex (all t ≥ 2.99, P of clusters <.002). The individuals with SPD also exhibited reduced activation in the anterior and middle cingulate cortices and the lingual and superior occipital gyri, which are brain areas responsive to biological motion perception and executive control of perception (all t ≥ 3.29, P of clusters <.001). In addition, significant correlations between the hyperdopaminergic clinical symptoms and enhanced neuronal activation in the caudate nucleus and frontal cortex were observed in the SPD group (all r ≥ 0.52, P < .02).Individuals with SPD display heightened activation in the neural circuitry involved in reward and decision making when viewing biological motion stimuli in addition to a positive correlation between increased blood oxygenation level-dependent signal responses related to biological motions and clinical symptoms. These findings suggest that enhanced responses arise within the reward network in individuals with SPD and are possibly related to the peculiar ways that individuals with SPD behave in social contexts.
Methionine restriction increases PC-3 cell uptake of MGBG
Authors: G. L. Chen, D. E. Epner
Journal: Journal of Clinical Oncology (2005)

2114 Background: Methylglyoxal-bis(guanylhydrazone) (MGBG) is an old chemotherapeutic agent with activity against hormone resistant prostate adenocarcinoma. It enters cells through the polyamine uptake system and inhibits spermidine and spermine synthesis. Intracellular polyamine levels are maintained by de novo synthesis and extracellular uptake. Methionine provides the propylamines needed to synthesize spermine and spermidine from putrescine. Its absence may cause decreased synthesis of spermine and spermidine resulting in increased uptake of spermine and spermidine to maintain intracellular polyamine levels. We examined the effect of methionine restriction on intracellular polyamine levels and the uptake of extracellular MGBG in PC-3 cells. Methods: PC-3 cells were cultured in methionine rich or poor medium with or without MGBG. Polyamines were extracted from PC-3 cells, tagged with benzoyl chloride, identified by HPLC, and quantified with UV absorption at 254 nm. MGBG was extracted from PC-3 cells, identified by HPLC, and quantified with UV absorption at 283 nm. Results: 24-hour methionine restriction of PC-3 cells increased putrescine levels to 299% of control, decreased spermidine levels to 90% of control, and decreased spermine levels to 54% of control. These levels were maintained at 48 hours of methionine restriction with putrescine, spermidine, and spermine levels at 277, 114, and 62% of control respectively. 24-hour methionine restriction of PC-3 cells exposed to MGBG increased intracellular MGBG levels to 173% of control. This effect was nullified by the addition of spermine and spermidine to the medium which decreased intracellular MGBG levels to 55% of control. Conclusions: Methionine restriction affects intracellular polyamine levels in PC-3 cells. When methionine is restricted, extracellular MGBG uptake is increased but nullified by extracellular spermine and spermidine. Certain tumor cell lines and explants are methionine dependent. In contrast, normal tissues are able to salvage methionine from its precursor homocysteine. Given this methionine auxotrophy, methionine restriction may be a potential method to preferentially target MGBG to tumors and warrants further investigation. No significant financial relationships to disclose.
Early oncologic outcomes after robotic assisted laparoscopic radical prostatectomy by D’Amico risk stratification
Authors: A. Akhavan, A. W. Levinson, D. S. Berkman, S. L. Rusnack, E. Goluboff, D. B. Samadi
Journal: Journal of Clinical Oncology (2008)

16114 Background: While the popularity of the Robotic Assisted Laparoscopic Prostatectomy (RALP) is assured, little is known about the oncologic outcomes of the procedure. We performed a prospective analysis of our oncologic outcomes using the risk stratification as proposed by D’Amico. Methods: We reviewed an IRB approved database of consecutive patients who received RALP between 2001 and 2007 by a single surgeon. For purposes of analysis, we limited our cohort to patients with at least 3 months follow-up. Based upon the risk stratification of D’Amico, we stratified patients into low, intermediate and high risk groups. We defined biochemical failure (BF) strictly as any PSA ≥ 0.2. No patient received adjuvant therapy prior to recurrence. We then calculated absolute and actuarial biochemical disease free survival (BDFS) for each of the risk groups. Results: 322 patients met inclusion criteria. Mean/median follow-up was 11.1/10.7 months (range 3.0–41.6). Mean preoperative PSA of 6.3/5.4 (range 0.45–48.6), median Gleason sum 6.0. Clinical stages were T1c in 225 (98%), T2a in 4 (2%). A total of 132 (42%), 160 (51%) and 24 (8%) were classified as low, intermediate, and high risk, respectively. Overall, 8% (25/322) experienced biochemical recurrence at a mean/median of 4.1/1.5 months (0.2 - 15.3). Absolute BDFS for low, intermediate, and high risk groups was 96%, 91%, and 79%, respectively (p = 0.0153). Actuarial 21 month survival for the three groups is 96%, 85%, 68%. In a multiple logistic regression model of individual variables, only preoperative PSA was independently predictive of biochemical failure, when controlling for pathologic stage, pathologic Gleason sum, and margin status (p < 0.001). Conclusions: Like other forms of radical prostatectomy, RALP provides excellent cancer control outcomes for clinically localized prostate cancer at short-term follow-up, with high actuarial biochemical disease free survival rates for all risk groups at 21 months. No significant financial relationships to disclose.
All BMJ research papers should share their analytic code
Authors: Ben Goldacre
Journal: BMJ (2016)

Freemantle and colleagues reject calls for them to share raw data from their controversial paper, citing privacy issues around individual patients’ records.1 2 They also note that large numbers of other researchers have access to the same electronic health record data they used (hospital episode statistics; HES).

This raises an important problem, often neglected in discussions on scientific transparency: the …
Abstract 9735: Endothelial Vasomotor Function in the Brachial Artery is Associated with Long-term Cardiovascular Events in Patients after Implantation of Drug Eluting-Stent
Authors: Yoshinobu Kitta, Takamitsu Nakamura, Manabu Uematsu, Wataru Sugamata, Juntaro Deyama, Daisuke Fujioka, Yukio Saito, Ken-ichi Kawabata, Jun-ei Obata, Kiyotaka Kugiyama
Journal: Circulation (2012)

Endothelial dysfunctionin systemic arteries is a predictor of long-term coronary events. Although drug eluting-stent (DES) implantation aggravates coronary artery endothelial vasomotor dysfunction, it remains unclear endothelial dysfunction in systemic arteries provides prognostic information in coronary artery disease (CAD) patients after implantation of DES. Thus, we examined whether endothelial dysfunction may predict future cardiovascular events in CAD patients after implantation of DES. Methods: This study included 231 consecutive patients with newly diagnosed CAD who had elective and successful PCI with DES in de novo lesions of native coronary arteries. Measurement of FMD (expressed as percent dilation from baseline brachial artery diameter) during reactive hyperemia was performed by high-resolution ultrasound at entry (before PCI) and after 6months. All patients had individualized, optimized therapies including medications and recommended life style changes to reduce risk factors for CAD according to AHA guidelines. Patients were prospectively followed up until the occurrence of 1 of the following events: cardiovascular death, recurrent or refractory angina pectoris, nonfatal myocardial infarction, and ischemic stroke. The impairment of FMD was defined as &lt; 5.5% (mean minus 1SD of FMD in 100 age- and sex-matched normal subjects in our hospital). Results: Impaired FMD (&lt;5.5%) was in 86 (37%) patients after 6months. During a follow-up period of 30 ± 0.8 months, events occurred in 19 patients of the 86 patients with impaired FMD after 6months. Using multivariate Cox hazards analysis, impaired FMD after 6months was a predictor of future cardiovascular events that was independent of impaired FMD at entry, use of medications, age, and traditional CAD risk factors (odds ratio 2.9, 95%CI 1.3 - 6.2, p &lt; 0.01) Conclusions: Endothelial dysfunction in the brachial artery represents an adverse outcome in CAD patients after implantation of DES. Measurement of FMD may be useful for risk stratification in CAD patients after implantation of DES.
Gefitinib reduces the production of osteoclast differentiation factors in human bone marrow stromal cells: Implications for treatment of bone metastasis
Authors: N. Normanno, A. de Luca, D. Aldinucci, M. R. Maiello, M. Mancino, A. D’Antonio, R. de Filippi, A. Pinto
Journal: Journal of Clinical Oncology (2005)

3119 Background: Clinical studies of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as monotherapy in breast cancer patients have shown some evidence of activity. Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the EGFR-TKI gefitinib (IRESSA) in patients with metastatic breast cancer. Methods: The expression and functional role of EGFR, as well as the effects of gefitinib (4 μM) on the ability to produce osteoclastogenic factors, were investigated by reverse-transcriptase PCR, Real-Time PCR, Western blot analysis, immunoprecipitation, and/or ELISAs in 2 human bone marrow-derived continuous mesenchymal-stem-cell-like cell lines, HDS-1 and HDS-2. Results: Immunohistochemical analysis of bone marrow biopsies showed that human primary bone marrow stromal cells (BMSC) express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in both HDS cell lines. The levels of activated EGFR were significantly increased in HDS cells following treatment with EGF; this activation was blocked by gefitinib. Gefitinib reduced basal levels of activated EGFR and Akt in HDS cells. Treatment of HDS cells with gefitinib significantly reduced levels of secreted macrophage colony-stimulating factor (p<0.001, Student t-test) and cell-associated receptor activator of NF-kB ligand (RANKL) [p<0.05, Student t-test]. In contrast, no significant effects of gefitinib on the secretion of osteoprotegerin, a RANKL decoy receptor that inhibits osteoclast differentiation, were observed in HDS cells. Finally, the ability of conditioned medium from gefitinib-treated HDS cells to sustain the differentiation of pre-osteoclasts was reduced by ∼45% compared with untreated HDS cells (p<0.001, Student t-test). Conclusions: These data demonstrate that EGFR regulates the ability of BMSC to induce osteoclast differentiation and strongly support clinical trials of gefitinib in patients with breast cancer and bone metastases. IRESSA is a trademark of the AstraZeneca group of companies Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
A novel multimodality endoscopic device for colonic submucosal dissection using a combination of bipolar radiofrequency and microwave modalities
Authors: Zacharias Tsiamoulos, Paul Sibbons, Steve Morris, Christopher Hancock, Brian Saunders
Journal: Endoscopy (2016)

<b>Background and study aims:</b> Current submucosal dissection devices are technically challenging to use, resulting in long and sometimes incomplete colonic polyp resections. The aim of this feasibility preclinical study was to evaluate a new, multimodality instrument with novel electrocautery properties. <b>Methods:</b> Six female adult pigs underwent colonic submucosal resections. The novel device was used to cut mucosa and submucosa using bipolar radiofrequency (BRF; at 400 KHz), provide hemostasis with microwave coagulation (MWC; at 5.8 GHz), and inject fluid via a retractable needle. The main outcomes measured were safety (histological analysis post-recovery), performance, and time needed to achieve complete resection. <b>Results:</b> A total of 12 consecutive colonic pseudopolyps were completely excised (two per subject) using BRF cutting. The median time to complete resection was 44.3 minutes (SD 8.9). The median defect size was 32.8 mm (SD 4.3). MWC was applied on 37 occasions for pre-coagulation or treatment of bleeding vessels. One microperforation was treated successfully with endoscopic clips. All animals recovered uneventfully during the 28-day survival period. Histology confirmed adequate healing in all postmortem defects. <b>Conclusions:</b> In this preclinical evaluation, the novel multimodality endoscopic device facilitated rapid and safe en bloc resection of colonic pseudopolyps.
Correlation of CD3 and CD34 cell dose with incidence of acute GVHD in myeloablative stem cell transplantation
Authors: A. Saad, N. Visweshwar, A. Sehbai, A. Cumpston, K. Watkins, R. Buckhalter, G. Hobbs, J. Abraham, S. Ericson
Journal: Journal of Clinical Oncology (2006)

6553 Background: Allogeneic stem cell transplantation is used to treat different types of hematologic malignancies. The target stem cell dose typically is based on the recipient’s ideal body weight (IBW) with CD34 dose of 2.0–5.0 ×10 6 /Kg. The dose of CD3 in the infusate is typically not taken into account in a stem cell product, except in T-depleted transplantation. The dose of T-cells in peripheral blood stem cell collections has been found to be at least 10-fold more than that in a bone marrow harvest product. Combined CD4+ and CD25+ cells infused have been directly correlated with increased incidence of GVHD. Methods: This is a retrospective study reporting the correlation of the CD34 and CD3 doses of stem cell transplant with incidence of acute GVHD in 67 consecutive patients who were treated between 2003 and 2005. All patients were followed up for at least 100 days following the stem cell transplant. Results: Among the 67 patients, 35 patients developed acute GVHD, while 32 patients had no evidence of acute GVHD. The CD3 and CD34 doses did not correlate. The correlation coefficient was 0.14 (P value: 0.27). Using t-test, there was NO statistical difference between the mean CD34 dose when comparing the group of patients who developed acute GVHD with the group that did not develop acute GVHD (P value: 0.31). Those who developed acute GVHD (n = 35) received a mean CD3 dose of 41.9 × 107/kg IBW (95% CI: 35.9–47.9). Those who did NOT develop acute GVHD (n= 32) received a mean CD3 dose of 33.5 × 107/kg IBW (95% CI: 27.3–39.8). By using the t-test, the P value for the different means was 0.0575. However, using a CD3 dose cutoff value of 30 × 107/kg IBW, the incidence of acute GVHD was statistically significantly less among those who received CD3 dose &lt; 30 × 107/kg IBW. The Chi Square P value was 0.04. Conclusions: In our series, CD3 dose less than 30 × 107/kg IBW was associated with reduced risk of acute GVHD (P value: 0.04). There was no correlation between CD3 and CD34 counts in peripheral stem cell product. In addition, the CD34 dose did not influence the incidence of acute GVHD. These data suggest that, in addition to considering CD34 dose required for engraftment in allogeneic transplant, the CD3 dose will need to be considered to try to minimize the risk of acute GVHD. No significant financial relationships to disclose.
Is differential T cell receptor patterning at the immune synapse mediated by glycosylation of the viral ligand UL18 and the inhibitory receptor ILT2?
Authors: Mina-Olga Aletrari, Keshalini Sabaratnam, Rui Zhang, Stephanie Dyball, Saeed Seyedmohammad, Marco A Purbhoo
Journal: The Lancet (2016)
Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task Force
Authors: Joy Melnikow, Joshua J. Fenton, Evelyn P. Whitlock, Diana L. Miglioretti, Meghan S. Weyrich, Jamie H. Thompson, Kunal Shah
Journal: Annals of Internal Medicine (2016)

Background: Screening mammography has lower sensitivity and specificity in women with dense breasts, who experience higher breast cancer risk. Purpose: To perform a systematic review of reproducibility of Breast Imaging Reporting and Data System (BI-RADS) density categorization and test performance and clinical outcomes of supplemental screening with breast ultrasonography, magnetic resonance imaging (MRI), and digital breast tomosynthesis (DBT) in women with dense breasts and negative mammography results. Data Sources: MEDLINE, PubMed, EMBASE, and Cochrane database from January 2000 to July 2015. Study Selection: Studies reporting BI-RADS density reproducibility or supplemental screening results for women with dense breasts. Data Extraction: Quality assessment and abstraction of 24 studies from 7 countries; 6 studies were good-quality. Data Synthesis: Three good-quality studies reported reproducibility of BI-RADS density; 13% to 19% of women were recategorized between "dense" and "nondense" at subsequent screening. Two good-quality studies reported that sensitivity of ultrasonography for women with negative mammography results ranged from 80% to 83%; specificity, from 86% to 94%; and positive predictive value (PPV), from 3% to 8%. The sensitivity of MRI ranged from 75% to 100%; specificity, from 78% to 94%; and PPV, from 3% to 33% (3 studies). Rates of additional cancer detection with ultrasonography were 4.4 per 1000 examinations (89% to 93% invasive); recall rates were 14%. Use of MRI detected 3.5 to 28.6 additional cancer cases per 1000 examinations (34% to 86% invasive); recall rates were 12% to 24%. Rates of cancer detection with DBT increased by 1.4 to 2.5 per 1000 examinations compared with mammography alone (3 studies). Recall rates ranged from 7% to 11%, compared with 7% to 17% with mammography alone. No studies examined breast cancer outcomes. Limitations: Good-quality evidence was sparse. Studies were small and CIs were wide. Definitions of recall were absent or inconsistent. Conclusion: Density ratings may be recategorized on serial screening mammography. Supplemental screening of women with dense breasts finds additional breast cancer but increases false-positive results. Use of DBT may reduce recall rates. Effects of supplemental screening on breast cancer outcomes remain unclear. Primary Funding Source: Agency for Healthcare Research and Quality.