tbuckley/cabot-search huggingface dataset:
Epigenetic inactivation of miR-9 family microRNAs in chronic lymphocytic leukemia - implications on constitutive activation of NFκB pathway
Authors: Lu Qian Wang, Yok Lam Kwong, Chi Shan Bonnie Kho, Kit Fai Wong, Kwan Yeung Wong, Manuela Ferracin, George A Calin, Chor Sang Chim
Journal: Molecular Cancer (2013)

The miR-9 family microRNAs have been identified as a tumor suppressor miRNA in cancers. We postulated that miR-9-1, miR-9-2 and miR-9-3 might be inactivated by DNA hypermethylation in chronic lymphocytic leukemia (CLL).Methylation of miR-9-1, miR-9-2 and miR-9-3 was studied in eight normal controls including normal bone marrow, buffy coat, and CD19-sorted peripheral blood B-cells from healthy individuals, seven CLL cell lines, and seventy-eight diagnostic CLL samples by methylation-specific polymerase chain reaction.The promoters of miR-9-3 and miR-9-1 were both unmethylated in normal controls, but methylated in five (71.4%) and one of seven CLL cell lines respectively. However, miR-9-2 promoter was methylated in normal controls including CD19 + ve B-cells, hence suggestive of a tissue-specific but not tumor-specific methylation, and thus not further studied. Different MSP statuses of miR-9-3, including complete methylation, partial methylation, and complete unmethylation, were verified by quantitative bisulfite methylation analysis. 5-Aza-2'-deoxycytidine treatment resulted in miR-9-3 promoter demethylation and re-expression of pri-miR-9-3 in I83-E95 and WAC3CD5+ cells, which were homozygously methylated for miR-9-3. Moreover, overexpression of miR-9 led to suppressed cell proliferation and enhanced apoptosis together with downregulation of NFκB1 in I83-E95 cells, supporting a tumor suppressor role of miR-9-3 in CLL. In primary CLL samples, miR-9-3 was detected in 17% and miR-9-1 methylation in none of the patients at diagnosis. Moreover, miR-9-3 methylation was associated with advanced Rai stage (≥ stage 2) (P = 0.04).Of the miR-9 family, miR-9-3 is a tumor suppressor miRNA relatively frequently methylated, and hence silenced in CLL; whereas miR-9-1 methylation is rare in CLL. The role of miR-9-3 methylation in the constitutive activation of NFκB signaling pathway in CLL warrants further study.
Severe fever with thrombocytopenia syndrome bunyavirus-related human encephalitis
Authors: Ning Cui, Rong Liu, Qing-Bin Lu, Li-Yuan Wang, Shu-Li Qin, Zhen-Dong Yang, Lu Zhuang, Kun Liu, Hao Li, Xiao-Ai Zhang, Jian-Gong Hu, Jing-Yu Wang, Wei Liu, Wu-Chun Cao
Journal: Journal of Infection (2014)
Letter by Tarantini et al Regarding Article, “Optimal Medical Therapy With or Without Percutaneous Coronary Intervention to Reduce Ischemic Burden: Results From the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Nuclear Substudy”
Authors: Giuseppe Tarantini, Renato Razzolini, Sabino Iliceto
Journal: Circulation (2008)
Noninvasive, Transthoracic, Low-Frequency Ultrasound Augments Thrombolysis in a Canine Model of Acute Myocardial Infarction
Authors: Robert J. Siegel, Shaul Atar, Michael C. Fishbein, Andrea V. Brasch, Thomas M. Peterson, Tomoo Nagai, Dharmendra Pal, Toshihiko Nishioka, Jang-Seong Chae, Yochai Birnbaum, Claudio Zanelli, Huai Luo
Journal: Circulation (2000)

Limitations of coronary thrombolysis include the time to reperfusion, patency rate, and bleeding. We evaluated the use of noninvasive transcutaneous ultrasound to augment coronary thrombolysis.In 24 dogs, a thrombotic occlusion of the left anterior descending coronary artery was induced and documented by 12-lead ECG and coronary angiography. After >/=60 minutes of occlusion, tissue-type plasminogen activator (t-PA; 1.42 mg/kg) was given intravenously over 90 minutes. A total of 12 of the 24 dogs had concomitant transcutaneous application of low-frequency ultrasound (27 kHz) over the chest. At 90 minutes, the mean TIMI grade flow in the t-PA alone group was 0.92+/-1.4 compared with 2. 42+/-1.9 in the t-PA plus ultrasound group (P=0.006). TIMI 2 to 3 flow was present in 4 of 12 cases receiving t-PA alone compared with 10 of 12 cases receiving t-PA plus ultrasound (P=0.003). At 180 minutes, mean TIMI grade flow was 0.75+/-1.4 in the t-PA alone group versus 2.58+/-0.9 in the t-PA plus ultrasound group (P=0.001). Pathological examination confirmed the angiographic patency rate and did not reveal injury secondary to ultrasound in the skin, soft tissues, heart, or lungs.In vivo, the noninvasive transthoracic application of low-frequency ultrasound (1) greatly augments the efficacy of t-PA-mediated thrombolysis, (2) seems safe, and (3) has substantial potential as a noninvasive adjunct to improve coronary patency without increasing the risk of bleeding.
Physical and Functional Interactions between Cas and c-Src Induce Tamoxifen Resistance of Breast Cancer Cells through Pathways Involving Epidermal Growth Factor Receptor and Signal Transducer and Activator of Transcription 5b
Authors: Rebecca B. Riggins, Keena S. Thomas, Huy Q. Ta, Jie Wen, Rebecca J. Davis, Natasha R. Schuh, Stacey S. Donelan, Katherine A. Owen, Matthew A. Gibson, Margaret A. Shupnik, Corinne M. Silva, Sarah J. Parsons, Robert Clarke, Amy H. Bouton
Journal: Cancer Research (2006)

Abstract High expression of the adaptor molecule Cas has been linked to resistance to the antiestrogen tamoxifen, both in tissue culture and in human tumors. The aim of this study was to elucidate the mechanism(s) by which overexpression of Cas confers resistance to tamoxifen. Cas overexpression in MCF-7 breast cancer cells was shown to alleviate both tamoxifen-mediated growth inhibition and induction of apoptosis. This enhancement of cell proliferation/survival occurred in the absence of detectable effects on estrogen receptor (ER) transcriptional activity under conditions where tamoxifen was present, indicating that Cas-dependent tamoxifen resistance is not the result of a switch to an ER-negative phenotype or enhanced responses to the partial agonist activity of tamoxifen. Instead, we present evidence, suggesting that Cas promotes tamoxifen resistance by deregulation of alternative cell proliferation pathways, particularly those mediated through enhanced c-Src protein tyrosine kinase activity arising from Cas/c-Src interactions. Overexpression of Cas was found to drive endogenous c-Src into complex with Cas, a process that has been shown previously to cause up-regulation of c-Src tyrosine kinase activity. MCF-7 cells overexpressing Cas exhibited increased phosphorylation of two c-Src substrates, Tyr845 in the kinase domain of the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription (STAT) 5b. Importantly, Cas-dependent protection from the antiproliferative effects of tamoxifen was reversed by the expression of dominant inhibitory variants of these substrates (Y845F EGFR and COOH-terminally truncated STAT5b). Based on these findings, we suggest that the Cas/c-Src/EGFR/STAT5 signaling axis is a major regulator of tamoxifen-resistant breast cancer cell growth and survival. (Cancer Res 2006; 66(14): 7007-15)
Don't Mess with the DSMB
Authors: Jeffrey M. Drazen, Alastair J.J. Wood
Journal: New England Journal of Medicine (2010)

If the lyrics of the popular Jim Croce song from the early 1970s were adapted for a clinical trialist anthem, the refrain would likely be You don't tug on Superman's cape You don't spit into the wind You don't pull the mask off that old Lone Ranger And you don't mess around with the DSMB. Since the DSMB (data and safety monitoring board) is charged with ensuring that clinical equipoise is maintained as trial data are accrued, it is considered very bad, even self-destructive, behavior for people who are involved with the study to interact with DSMB members on trial-related . . .
Ca <sup>2+</sup> Handling and Sarcoplasmic Reticulum Ca <sup>2+</sup> Content in Isolated Failing and Nonfailing Human Myocardium
Authors: Burkert Pieske, Lars S. Maier, Donald M. Bers, Gerd Hasenfuss
Journal: Circulation Research (1999)

Abstract —Disturbed sarcoplasmic reticulum (SR) Ca 2+ content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca 2+ content in ventricular muscle strips isolated from nonfailing and end-stage failing human hearts. With an increase in rest intervals (1 to 240 s; 37°C), nonfailing human myocardium (n=7) exhibited a parallel increase in postrest twitch force (at 240 s by 121±44%; P &lt;0.05) and RCC amplitude (by 69±53%; P &lt;0.05). In contrast, in failing myocardium (n=30), postrest twitch force decreased at long rest intervals and RCC amplitude declined monotonically with rest (by 25±9% and 53±9%, respectively; P &lt;0.05). With an increase in stimulation frequencies (0.25 to 3 Hz), twitch force increased continuously in nonfailing human myocardium (n=7) by 71±17% (at 3 Hz; P &lt;0.05) and RCC amplitude increased in parallel by 247±55% ( P &lt;0.05). In contrast, in failing myocardium (n=26), twitch force declined by 29±7% ( P &lt;0.05) and RCC amplitude increased only slightly by 36±14% ( P &lt;0.05). Paired RCCs were evoked to investigate the relative contribution of SR Ca 2+ uptake and Na + /Ca 2+ exchange to cytosolic Ca 2+ removal during relaxation. SR Ca 2+ uptake (relative to the Na + /Ca 2+ exchange) increased significantly in nonfailing but not in failing human myocardium as stimulation rates increased. We conclude that the negative force-frequency relation in failing human myocardium is due to an inability of SR Ca 2+ content to increase sufficiently at high frequencies and thus cannot overcome the frequency-dependent refractoriness of SR Ca 2+ release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca 2+ content. These alterations could be secondary to depressed SR Ca 2+ -ATPase combined with enhanced cytosolic Ca 2+ extrusion via Na + /Ca 2+ exchange.
The multiple effects of tumour necrosis factor inhibitors on immune cells: new insights on inhibition of activation and cycling: Figure 1
Authors: Matthieu Allez
Journal: Gut (2012)

Together with immunosuppressants, anti-tumour necrosis factor (TNF) monoclonal antibodies represent a major class of treatment for the inflammatory bowel diseases (IBD) therapeutic arsenal. Almost 20 years after the first report of infliximab in Crohn's disease,1 we do not know exactly how these TNF inhibitors control the inflammatory response, and their mechanism of action is still a matter of investigation.

Werner et al 2 show that infliximab and adalimumab not only induce T-cell apoptosis but also inhibit T-cell function, activation and cycling (see page 1016) . They demonstrate that while T-cell apoptosis is mediated by TNF signalling, the inhibition of T-cell activation and cycling is not dependent on TNF signalling but on Notch-1 signalling. They thereby provide new insights on the mechanisms of action of TNF inhibitors, and more specifically on T cells.

Anti-TNF monoclonal antibodies bind and neutralise TNF, and downregulate the inflammatory response, through suppression of pro-inflammatory cytokine secretion, inhibition of chemokine secretion and downregulation of adhesion molecules. These effects can be mediated by direct neutralisation of soluble TNF and interaction with membrane-bound TNF. Furthermore, TNF inhibitors clearly participate in the elimination and clearance of active inflammatory cells from inflamed tissue. This can be achieved by a number of mechanisms including apoptosis induction, antibody and complement-mediated cytotoxicity and inhibition of cell migration into the intestinal tissue. Many leucocyte and endothelial adhesion molecules as well as leucocyte chemokine receptors and endothelial chemokines are upregulated in the inflamed mucosa of IBD patients. It was recently shown that most of these molecules are downregulated in infliximab responders.3

It is clear that anti-TNF agents can induce the apoptosis of active inflammatory cells. In vitro, both infliximab and adalimumab induce …
Increased frequency of supraventricular (SVPC) and ventricular arrhythmias (PVC) in stable patients with chronic obstructive pulmonary disease (COPD)
Authors: Yuji Kusunoki, Kumiko Hattori, Toshie Nakamura, Takashi Motegi, Takeo Ishii, Ryuko Furutate, Akihiko Genma, Kozui Kida
Journal: European Respiratory Journal (2014)

Background: Clinical significance of both SVPC and PVC in COPD is noteworthy in therapy.

Aim: We investigated the association between frequency of SVPC and PVC, and pulmonary function, exercise capacity and emphysema severity on chest computed-tomography (LAA%).

Methods: Stable COPD or symptomatic patients (n=135) recruited who had arrhythmia on a 12-lead ECG or chest symptoms such as palpitation. The patients (n=103, men 90, mean age 68.8 years), excluded receiving anti-arrhythmia medications, underwent pulmonary function tests, 24 hr-ECG, echocardiogram, LAA% and 6 minutes walking test (6MWT).

Results: 24-hour heart rate increased with FEV1%pred (r=-0.337, p<0.001). Both frequency of SVPC and PVC were significantly associated with severity of airflow obstruction; the SVPC and PVC for FEV1%pred (odds ratio 1.030, 95%CI 1.01-1.05, p<0.001) and (1.036, 1.01-1.05, p<0.000), respectively. The frequency of PVC increased with LAA% (0.957, 0.92-0.98, p<0.003), pressure of right ventricle (0.917, 0.85-0.97, p<0.003) and nadir oxygen saturation in 6MWT (1.114, 1.03-1.21, p<0.006). Whereas, the frequency of SVPC increased with LAA% (0.971, 0.94-0.99, p<0.03). The frequency of SVPC was significantly associated with taking medications, including anti-cholinergic (0.286, 0.12-0.64, p<0.003),β2 agonist (0.267, 0.10-0.63, p<0.003) and theophylline (0.208, 0.06-0.60, p<0.004), respectively, but not with PVC.

Conclusions: Frequency of SVPC and PVC increases with severity of COPD. Increased of PVC frequency is affected by right ventricular pressure and hypoxemia on exertion. And increased of SVPC frequency is affected by use of bronchodilators.
Zinc Supplement Use and Risk of Prostate Cancer
Authors: M. F. Leitzmann, M. J. Stampfer, K. Wu, G. A. Colditz, W. C. Willett, E. L. Giovannucci
Journal: JNCI Journal of the National Cancer Institute (2003)

The high concentration of zinc in the prostate suggests that zinc may play a role in prostate health. We examined the association between supplemental zinc intake and prostate cancer risk among 46 974 U.S. men participating in the Health Professionals Follow-Up Study. During 14 years of follow-up from 1986 through 2000, 2901 new cases of prostate cancer were ascertained, of which 434 cases were diagnosed as advanced cancer. Supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, compared with nonusers, men who consumed more than 100 mg/day of supplemental zinc had a relative risk of advanced prostate cancer of 2.29 (95% confidence interval = 1.06 to 4.95; P(trend) =.003), and men who took supplemental zinc for 10 or more years had a relative risk of 2.37 (95% confidence interval = 1.42 to 3.95; P(trend)<.001). Although we cannot rule out residual confounding by supplemental calcium intake or some unmeasured correlate of zinc supplement use, our findings, that chronic zinc oversupply may play a role in prostate carcinogenesis, warrant further investigation.
Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors
Authors: Shu Zhang, Curt Balch, Michael W. Chan, Hung-Cheng Lai, Daniela Matei, Jeanne M. Schilder, Pearlly S. Yan, Tim H-M. Huang, Kenneth P. Nephew
Journal: Cancer Research (2008)

Abstract The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals. Ovarian serous adenocarcinomas were disaggregated and subjected to growth conditions selective for self-renewing, nonadherent spheroids previously shown to derive from tissue stem cells. To affirm the existence of OCICs, xenoengraftment of as few as 100 dissociated spheroid cells allowed full recapitulation of the original tumor (grade 2/grade 3 serous adenocarcinoma), whereas &amp;gt;105 unselected cells remained nontumorigenic. Stemness properties of OCICs (under stem cell–selective conditions) were further established by cell proliferation assays and reverse transcription–PCR, demonstrating enhanced chemoresistance to the ovarian cancer chemotherapeutics cisplatin or paclitaxel and up-regulation of stem cell markers (Bmi-1, stem cell factor, Notch-1, Nanog, nestin, ABCG2, and Oct-4) compared with parental tumor cells or OCICs under differentiating conditions. To identify an OCIC cell surface phenotype, spheroid immunostaining showed significant up-regulation of the hyaluronate receptor CD44 and stem cell factor receptor CD117 (c-kit), a tyrosine kinase oncoprotein. Similar to sphere-forming OCICs, injection of only 100 CD44+CD117+ cells could also serially propagate their original tumors, whereas 105 CD44−CD117− cells remained nontumorigenic. Based on these findings, we assert that epithelial ovarian cancers derive from a subpopulation of CD44+CD117+ cells, thus representing a possible therapeutic target for this devastating disease. [Cancer Res 2008;68(11):4311–20]
Associations of High-Grade Prostate Cancer with <i>BRCA1</i> and <i>BRCA2</i> Founder Mutations
Authors: Ilir Agalliu, Robert Gern, Suzanne Leanza, Robert D. Burk
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Protein-truncating mutations in BRCA1 and in particular BRCA2 genes have been associated with prostate cancer. However, there is still uncertainty about the magnitude of association particularly with Gleason score, and family history of prostate, breast, and ovary cancers. Experimental Design: To further examine associations between three founder mutations located in BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) genes and prostate cancer, we conducted a study of 979 prostate cancer cases and 1,251 controls among Ashkenazi Jewish men. Detailed information was obtained on prostate cancer pathology, age at diagnosis, and family history of all cancers. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression models. Results: Prostate cancer risk was increased (OR, 1.9; 95% CI 0.9-4.1) for BRCA2 mutation carriers but not for BRCA1 mutation carriers. BRCA2 mutation carriers had an OR of 3.2 (95% CI, 1.4-7.3) for Gleason score of 7 to 10, but no association was observed for Gleason score of &amp;lt;7. Carriers of BRCA1-185delAG mutation also had an OR of 3.5 (95% CI, 1.2-10.3) for Gleason score of ≥7 tumors; however, the association of either BRCA1-185delAG or 5382insC mutation was not statistically significant. Associations between founder mutations and prostate cancer were stronger in men with no first-degree family history of breast and/or ovarian cancers but were unaffected by family history of prostate cancer. Conclusion: These results indicate that the BRCA2 founder mutation confers a 3-fold elevated risk of high-grade prostate cancer. Although BRCA1 mutations were not associated with prostate cancer, the BRCA1-185delAG was associated with high Gleason score tumors. These findings should be carefully considered in genetic counseling and/or evaluating therapeutic options.
Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling
Authors: Jacob M Basak, Jungsu Kim, Yuriy Pyatkivskyy, Kristin R Wildsmith, Hong Jiang, Maia Parsadanian, Bruce W Patterson, Randall J Bateman, David M Holtzman
Journal: Molecular Neurodegeneration (2012)

Abstract Background Abnormal proteostasis due to alterations in protein turnover has been postulated to play a central role in several neurodegenerative diseases. Therefore, the development of techniques to quantify protein turnover in the brain is critical for understanding the pathogenic mechanisms of these diseases. We have developed a bolus stable isotope-labeling kinetics (SILK) technique coupled with multiple reaction monitoring mass spectrometry to measure the clearance of proteins in the mouse brain. Results Cohorts of mice were pulse labeled with 13 C 6 -leucine and the brains were isolated after pre-determined time points. The extent of label incorporation was measured over time using mass spectrometry to measure the ratio of labeled to unlabeled apolipoprotein E (apoE) and amyloid β (Aβ). The fractional clearance rate (FCR) was then calculated by analyzing the time course of disappearance for the labeled protein species. To validate the technique, apoE clearance was measured in mice that overexpress the low-density lipoprotein receptor (LDLR). The FCR in these mice was 2.7-fold faster than wild-type mice. To demonstrate the potential of this technique for understanding the pathogenesis of neurodegenerative disease, we applied our SILK technique to determine the effect of ATP binding cassette A1 (ABCA1) on both apoE and Aβ clearance. ABCA1 had previously been shown to regulate both the amount of apoE in the brain, along with the extent of Aβ deposition, and represents a potential molecular target for lowering brain amyloid levels in Alzheimer's disease patients. The FCR of apoE was increased by 1.9- and 1.5-fold in mice that either lacked or overexpressed ABCA1, respectively. However, ABCA1 had no effect on the FCR of Aβ, suggesting that ABCA1 does not regulate Aβ metabolism in the brain. Conclusions Our SILK strategy represents a straightforward, cost-effective, and efficient method to measure the clearance of proteins in the mouse brain. We expect that this technique will be applicable to the study of protein dynamics in the pathogenesis of several neurodegenerative diseases, and could aid in the evaluation of novel therapeutic agents.
Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study
Authors: Smita Bhatia, Leslie L. Robison, Liton Francisco, Andrea Carter, Yan Liu, Marcia Grant, K. Scott Baker, Henry Fung, James G. Gurney, Philip B. McGlave, Auayporn Nademanee, Norma K. C. Ramsay, Anthony Stein, Daniel J. Weisdorf, Stephen J. Forman
Journal: Blood (2005)