tbuckley/cabot-search huggingface dataset:
Phase I-II trial of weekly bicalutamide in men with high PSA and negative biopsy
Authors: A. Decensi, S. Zanardi, M. Puntoni, R. Bandelloni, D. Branchi, A. Argusti, F. Campodonico, L. Turbino, M. Mori, M. Maffezzini
Journal: Journal of Clinical Oncology (2007)

1500 Background: Men with persistent PSA elevation after non-cancer findings are at high risk of prostate cancer (PC). Bicalutamide (Bic) is an androgen receptor antagonist, which, unlike finasteride, is not associated with testosterone (T) escape. Given its long half-life (6–8 days), allowing for a weekly administration with potentially reduced side effects, Bic may be a suitable chemopreventive agent. We assessed the activity and safety of a weekly low-dose Bic in a phase I-II study in subjects with PSA &gt;4 ng/ml and no PC at initial biopsies (10- 12 cores). Methods: Eligible subjects were sequentially assigned to either Bic 50 mg/week (group A), or 100 mg/week (group B), or no treatment (group C) for 6 mos. The outcome measures were the 6 mos changes in tissue Ki67 (primary endpoint), topoisomerase-IIa, Bcl- 2, and COX-2 by IHC, morphology and circulating PSA, prostatic acid phosphatase (PAP) and hormones. Results: From May, 2004 to June, 2006, 107 subjects were screened and 80 were enrolled: 26 in group A, 28 in group B, and 26 in group C. High-grade (HG) PIN decreased from 32% to 23% in the treated group and increased from 24% to 34% in controls; proliferative inflammatory atrophia (PIA) decreased from 41% to 32% in the treated group and increased from 14% to 19% in the controls. Complete remission of HG-PIN was found in 10/14 treated subjects versus 1/5 controls. Cancer or HG-PIN were found in 11 control subjects (52%) versus 16 subjects (36%) in the treated arms at 6 mos. Ki67 expression was significantly higher in HG-PIN lesions than in normal tissue (12% vs. 3%, p&lt;0.01), but it was not modulated by Bic. Bcl-2 expression in normal tissue was 0/1+ in most subjects, and increased in 36% of treated subjects versus 20% of controls. Total and free PSA, as well as PAP, decreased by &gt;30% on Bic. T, LH, estradiol and SHBG increased on Bic by 50–60%. There was no dose-related modulation in any biomarker. Treatment was well tolerated, mild (G1) breast pain and gynecomastia being recorded in 40% of treated subjects. Conclusions: Weekly Bic is active and safe in subjects with high PSA and negative biopsy. It seems to be associated with HG- PIN remission, Bcl-2 overexpression and a favorable modulation of PSA. The dose of 50 mg/week should be selected for future chemoprevention trials. No significant financial relationships to disclose.
Bidirectional cross-regulation between ErbB2 and β-adrenergic signalling pathways
Authors: Polina Sysa-Shah, Carlo G. Tocchetti, Manveen Gupta, Peter P. Rainer, Xiaoxu Shen, Byung-Hak Kang, Frances Belmonte, Jian Li, Yi Xu, Xin Guo, Djahida Bedja, Wei Dong Gao, Nazareno Paolocci, Rutwik Rath, Douglas B. Sawyer, Sathyamangla V. Naga Prasad, Kathleen Gabrielson
Journal: Cardiovascular Research (2015)

AimsDespite the observation that ErbB2 regulates sensitivity of the heart to doxorubicin or ErbB2-targeted cancer therapies, mechanisms that regulate ErbB2 expression and activity have not been studied. Since isoproterenol up-regulates ErbB2 in kidney and salivary glands and β2AR and ErbB2 complex in brain and heart, we hypothesized that β-adrenergic receptors (AR) modulate ErbB2 signalling status.
Concomitant JAK2 V617F-positive polycythemia vera and BCR-ABL-positive chronic myelogenous leukemia treated with ruxolitinib and dasatinib
Authors: A Zhou, E M Knoche, E K Engle, D A C Fisher, S T Oh
Journal: Blood Cancer Journal (2015)

Concomitant  JAK2  V617F-positive polycythemia vera and  BCR-ABL -positive chronic myelogenous leukemia treated with ruxolitinib and dasatinib
Exercise induced bronchoconstriction in adults: evidence based diagnosis and management
Authors: James M Smoliga, Pnina Weiss, Kenneth W Rundell
Journal: BMJ (2016)

#### What you need to know

EIB is defined as “the transient narrowing of the lower airway following exercise in the presence or absence of clinically recognized asthma.”1 Bronchoconstriction typically develops within 15 minutes after exercise and spontaneously resolves within 60 minutes. After an episode of EIB, there is often a refractory period of about 1-3 hours in which, if exercise is repeated, the bronchoconstriction is less emphasised in 40-50% of patients.2 3 EIB can also occur during exercise.4 5

The term “exercise induced bronchoconstriction” is preferred to that of “exercise induced asthma” since asthma is a chronic condition which is not induced by a single bout of exercise. EIB is more likely in people with asthma, but it also occurs in individuals without asthma.1 6 EIB is characterised by falls in forced expiratory volume in one second (FEV1) after exercise, while in people with asthma there is persistent airway inflammation and recurrent symptoms outside of exercise (that is, …
Poor vision in a patient with white hair and pale skin
Authors: Koushik Tripathy, Yog Raj Sharma
Journal: BMJ (2016)

A 26 year old man presented with poor vision in both eyes since childhood. He had white hair and pale skin. He had a best corrected vision of 5/60 in each eye and horizontal nystagmus. What is the diagnosis when the photos of the anterior segment (A⇓) and fundus …
Comparison between clinical response and in vitro drug sensitivity of primary human tumors in the adhesive tumor cell culture system.
Authors: J A Ajani, F L Baker, G Spitzer, A Kelly, W Brock, B Tomasovic, S E Singletary, M McMurtrey, C Plager
Journal: Journal of Clinical Oncology (1987)

The newly described adhesive tumor cell culture system (ATCCS) offers a distinct advantage over other assays in that it has a high plating efficiency requiring low cell inoculum, it affords workable assays in approximately 70% of specimens from the heterogenous tumor types, and it has the ability to assay up to nine drugs at four different concentrations. Clinical correlations based on the ATCCS were obtained in 65 patients undergoing 71 clinical trials. Patients with melanoma, lung cancer, and sarcoma dominated the group. The most active in vitro drug was correlated per clinical trial. Thirteen of 17 (76%) sensitive in vitro predictions and 51 of 54 (94%) resistant in vitro predictions were accurate. The assay in this study had a sensitivity of 81% and specificity of 93%. These preliminary results are encouraging and warrant prospective trials to establish the true value of this assay to patients.
Non-Myeloablative Conditioning Targeting Host Immunosuppression Is Successful in Matched Sibling Donor Stem Cell Transplantation for Hemoglobinopathies in Children
Authors: Allison A King, Nancy Bunin, Indira Sahdev, Joel A Brochstein, Allistair Abraham, Jacqueline Dioguardi, Naynesh R. Kamani, Eric Jon Anderson, Jennifer Willert, Ka Wah Chan, Michael Grimley, Dorothea N. Douglas, Roberta H. Adams, Sonali Chaudhury, Lolie C. Yu, Andrew Gilman, Martin Andreansky, Geoff D. E. Cuvelier, Alfred P. Gillio, Kimberly A. Kasow, Paul R. Haut, Gregory A. Hale, Jignesh Dalal, Akshat Jain, Eric Hanson, Lisa. Murray, Shalini Shenoy
Journal: Blood (2014)
Genome-wide Profiling Reveals Remarkable Parallels Between Insertion Site Selection Properties of the MLV Retrovirus and the piggyBac Transposon in Primary Human CD4+ T Cells
Authors: Andreas Gogol-Döring, Ismahen Ammar, Saumyashree Gupta, Mario Bunse, Csaba Miskey, Wei Chen, Wolfgang Uckert, Thomas F Schulz, Zsuzsanna Izsvák, Zoltán Ivics
Journal: Molecular Therapy (2016)

The inherent risks associated with vector insertion in gene therapy need to be carefully assessed. We analyzed the genome-wide distributions of Sleeping Beauty (SB) and piggyBac (PB) transposon insertions as well as MLV retrovirus and HIV lentivirus insertions in human CD4+ T cells with respect to a panel of 40 chromatin states. The distribution of SB transposon insertions displayed the least deviation from random, while the PB transposon and the MLV retrovirus showed unexpected parallels across all chromatin states. Both MLV and PB insertions are enriched at transcriptional start sites (TSSs) and co-localize with BRD4-associated sites. We demonstrate physical interaction between the PB transposase and bromodomain and extraterminal domain proteins (including BRD4), suggesting convergent evolution of a tethering mechanism that directs integrating genetic elements into TSSs. We detect unequal biases across the four systems with respect to targeting genes whose deregulation has been previously linked to serious adverse events in gene therapy clinical trials. The SB transposon has the highest theoretical chance of targeting a safe harbor locus in the human genome. The data underscore the significance of vector choice to reduce the mutagenic load on cells in clinical applications. The inherent risks associated with vector insertion in gene therapy need to be carefully assessed. We analyzed the genome-wide distributions of Sleeping Beauty (SB) and piggyBac (PB) transposon insertions as well as MLV retrovirus and HIV lentivirus insertions in human CD4+ T cells with respect to a panel of 40 chromatin states. The distribution of SB transposon insertions displayed the least deviation from random, while the PB transposon and the MLV retrovirus showed unexpected parallels across all chromatin states. Both MLV and PB insertions are enriched at transcriptional start sites (TSSs) and co-localize with BRD4-associated sites. We demonstrate physical interaction between the PB transposase and bromodomain and extraterminal domain proteins (including BRD4), suggesting convergent evolution of a tethering mechanism that directs integrating genetic elements into TSSs. We detect unequal biases across the four systems with respect to targeting genes whose deregulation has been previously linked to serious adverse events in gene therapy clinical trials. The SB transposon has the highest theoretical chance of targeting a safe harbor locus in the human genome. The data underscore the significance of vector choice to reduce the mutagenic load on cells in clinical applications.
Abstract 9919: PH-low Insertion Peptide (pHLIP) Targets Ischemic Myocardium
Authors: Oleg A Andreev, Evgeny P Anyukhovsky, Alexandre A Sosunov, Anna Moshnikova, Yana Reshetnyak, Eugene A Sosunov
Journal: Circulation (2012)

pHLIP molecule (∼3 kD) inserts into a lipid bilayer when ambient pH is low. Originally, this property was used for targeted delivery of small molecules, liposomes and nanoparticles conjugated with pHLIP to visualize and treat tumors. Since cardiac ischemia causes a decrease in tissue pH we hypothesized that pHLIP can selectively bind to ischemic myocardium. METHODS. We studied pH-sensitive (Var7) and a pH-insensitive (kVar7) variants of pHLIP conjugated with fluorescent dye Alexa488 in three models. (1) Local myocardial ischemia was induced by repetitively occluding (10 min) and reperfusing (5 s) left coronary artery of anesthetized mice for 2 hr; 100 μL of 80 μM pHLIP were administered IV 3 min prior to the first occlusion. In the end, hearts were excised and retrogradely perfused with Evans Blue to delineate the area at risk. Hearts were frozen and sectioned to measure mean intensity of fluorescence (F). (2) Low flow (5% of normal flow rate) global ischemia was induced in Langendorff-perfused mouse hearts paced at 5 Hz and perfused with 1 μM pHLIP for 15 min. (3) Effects of 10 μM pHLIP on transmembrane potential and developed force were studied in isolated preparations of paced (4 Hz) murine left atrial appendages (AA) at normal and low (6.5) pH. RESULTS. In the model of local ischemia, when pH-sensitive Var7 was used, area of bright fluorescence coincided with the area at risk. F in the area at risk normalized to F in intact myocardium was higher with Var7 (3.89±.43, n=4) than with pH-insensitive kVar7 (1.11±.09, n=5, p.05). In global ischemia, F was higher in the hearts perfused with Var7 vs either kVar7 or Var7 in the absence of ischemia (Var7: 76±8, n=5; kVar7: 25±5, n=4; Var7 + no ischemia: 12±4, n=3, p&lt;.05). In AA exposed to pH 6.5 (but not at pH 7.4), F was higher with Var7 than with kVar7 (76±9 vs 28±3, n=5; p&lt;.05). Neither at the normal or low pH, pHLIP variants affected parameters of transmembrane potential or developed force. CONCLUSIONS. pH-sensitive pHLIP selectively binds to ischemic myocardium without affecting either ectrical or mechanical activity. Based on analogy with applications in oncology, pHLIP can be used for targeted delivery of contrasting agents and drugs to ischemic regions of the heart.
Abstract 18522: Atrial Ganglionated Plexus Stimulation Prevents Myocardial Ischemia Reperfusion Arrhythmias by Preserving Connexin43 Protein
Authors: Lilei Yu, Wenbo He, Bing Huang, Bo He, Hong Jiang
Journal: Circulation (2012)

Atrial ganglionated plexus Stimulation Prevents Myocardial Ischemia Reperfusion Arrhythmias by Preserving Connexin43 Protein Background: Vagal nerve stimulation has been shown to provide protective effect against ischemia/reperfusion (I/R) arrhythmias. Since atrial epicardial ganglionated plexuses contain a large amount of parasympathetic elements, we hypothesize atrial epicardial ganglionated plexus stimulation (GP-S) may be an alternative to vagal nerve stimulation for preventing arrhythmias induced by myocardial I/R. Methods and Results: Twenty one dogs were randomly divided into GP stimulation (GP-S) group (N=11) and control group (N=10). Myocardial I/R was induced by first 2 hours of reperfusion in dogs subjected to 45 minutes of ischemia with occlusion of the left anterior descending coronary artery (LAD). A bipolar plaque electrode was sutured overlying the fad pad containing the superior left ganglionated plexus (SLGP), which located at the junction of left pulmonary artery and left superior pulmonary vein.The GP-S was performed by applying high frequency electrical stimulation (HFS: 20Hz, 0.1msec duration) to the SLGP. The lowest voltage level of GP-S that induced approximately 10% sinus rhythm slowing was chosen as the voltage for GP-S. Compared with control group, GP-S caused significant increases in ventricular ERP and vagal indice (HF nu), as well as an evident decrease in sympathetic tone (LF/HF), the numbers of PVCs, salvos, and VT runs were significantly reduced in GP-S group. And the incidences of salvo and VT in GP-S group were significantly lower. Immunoblotting revealed that the control group showed a marked reduction in the amount of phosphorylated connexin43 (Cx43), whereas the GP-S group showed only a slight reduction. Immunohistochemistry confirmed that the myocardial I/R-induced loss of Cx43 from intercellular junctions was prevented by GP-S. Conclusions: GP-S protects against ventricular arrhythmias resulting from brief myocardial I/R by modulating connexin43. GP-S may serve as a non-pharmacological clinical approach to improve acute myocardial I/R arrhythmias such as during coronary bypass surgery.
Highly Fluorescent and Photostable Polymeric Nanofibers as Scaffolds for Cell Interfacing and Long‐Term Tracking
Authors: Hua Jia Diao, Kai Wang, Hong Yan Long, Mingfeng Wang, Sing Yan Chew
Journal: Advanced Healthcare Materials (2016)

Highly fluorescent polymeric nanofibers fabricated via electrospinning of PCL-DPP-PCL (photostable polycaprolactones–di(thiophene-2-yl)-diketopyrrolopyrrole–photostable polycaprolactones) and commercial PCL mixture show superior photostability and cytocompatibility for long-term tracking of cell–substrate interaction. As a proof of concept, these PCL-DPP-PCL nanofibers enable clear visualization of intricate cell–substrate interactions such as oligodendrocyte myelination. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples
Authors: Manuel Valero, Elena Cid, Robert G Averkin, Juan Aguilar, Alberto Sanchez-Aguilera, Tim J Viney, Daniel Gomez-Dominguez, Elisa Bellistri, Liset Menendez de la Prida
Journal: Nature Neuroscience (2015)
Acetyl‐coenzyme A carboxylase alpha promotion of glucose‐mediated fatty acid synthesis enhances survival of hepatocellular carcinoma in mice and patients
Authors: Ming‐Da Wang, Han Wu, Gong‐Bo Fu, Hui‐Lu Zhang, Xu Zhou, Liang Tang, Li‐Wei Dong, Chen‐Jie Qin, Shuai Huang, Ling‐Hao Zhao, Min Zeng, Meng‐Chao Wu, He‐Xin Yan, Hong‐Yang Wang
Journal: Hepatology (2015)

Solid tumors often suffer from suboptimal oxygen and nutrient supplies. This stress underlies the requirement for metabolic adaptation. Aberrantly activated de novo lipogenesis is critical for development and progression of human hepatocellular carcinoma (HCC). However, whether de novo lipogenesis influences biological behaviors of HCCs under conditions of metabolic stress are still poorly understood. Here, we show that HCCs display distinct levels of glucose‐derived de novo lipogenesis, which are positively correlated with their survival responses to glucose limitation. The enhanced lipogenesis in HCCs is characterized by an increased expression of rate‐limiting enzyme acetyl‐coenzyme A carboxylase alpha (ACCα). ACCα‐mediated fatty acid (FA) synthesis determines the intracellular lipid content that is required to maintain energy hemostasis and inhibit cell death by means of FA oxidation (FAO) during metabolic stress. In accord, overexpression of ACCα facilitates tumor growth. ACCα forms a complex with carnitine palmitoyltransferase 1A (CPT1A) and prevents its mitochondria distribution under nutrient‐sufficient conditions. During metabolic stress, phosphorylation of ACCα leads to dissociation of the complex and mitochondria localization of CPT1A, thus promoting FAO‐mediated cell survival. Therefore, ACCα could provide both the substrate and enzyme storage for FAO during glucose deficiency. Up‐regulation of ACCα is also significantly correlated with poorer overall survival and disease recurrence postsurgery. Multivariate Cox's regression analysis identified ACCα as an effective predictor of poor prognosis. Conclusion: These results present novel mechanistic insight into a pivotal role of ACCα in maintaining HCC survival under metabolic stress. It could be exploited as a novel diagnostic marker and therapeutic target. (H epatology 2016;63:1272–1286)
Ham Test For Therapeutic Monitoring Of Eculizumab In Paroxysmal Nocturnal Hemoglobinuria
Authors: Miriam Arcavi, Fernanda Ceballo, Andres L. Brodsky, Nora Silvia Halperin, Norma Cantenys, Laura Beatriz Colin, Cecilia Malusardi, Alberto Lazarowski
Journal: Blood (2013)
Spending (slightly) less on health and more on the arts : Robust research is needed
Authors: Christine M Hamilton, Mark Petticrew
Journal: BMJ (2003)

Editor—Smith raises some important issues about the role of arts in our society and on the relative value we attach to arts and health, as reflected in their budgets.1 Perhaps a move to divert some modest funding from the health budget into the arts might prove more popular if some positive health benefit can be shown. But, despite the experiences of Simon Rattle (and any artist who has engaged with poverty and exclusion), the health benefits of the arts are not immediately obvious.

Although we might agree with Brown on bmj.com that the arts have positive effects in a hospital environment, there is a lack of robust evidence of the arts providing such benefits in other areas.2,3

The potential health benefits of participating in the arts to individual people and to the community have received widespread attention in recent years. The arts have been used as a medium for health promotion and as therapeutic interventions; in the case of the United Kingdom, health action zones and social inclusion partnerships arts projects have been used specifically to tackle social exclusion. As with other healthcare and social interventions, the arts might have an impact on health, but such impacts need to be shown, whether the outcomes are improvements in specific health outcomes or increases in rates of social participation.

Perhaps now that the BMJ has put the issue on the agenda, the door will open to supporting research in this area.
Incidence of Colorectal Neoplasia in a High Risk Population Screened for Colorectal Cancer. Result of 5 Consecutives Mass Screening Campaigns in a Well-Defined Population
Authors: S. Manfredi, J.F. Bretagne, G. Durand, C. Piette, G. Mallard, J. Faivre
Journal: Annals of Oncology (2014)
Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress
Authors: Samer Tohme, Hamza O. Yazdani, Ahmed B. Al-Khafaji, Alexis P. Chidi, Patricia Loughran, Kerri Mowen, Yanming Wang, Richard L. Simmons, Hai Huang, Allan Tsung
Journal: Cancer Research (2016)

Abstract Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a &amp;gt;4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil–derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse. Cancer Res; 76(6); 1367–80. ©2016 AACR.
Additive Value of Integrated Backscatter IVUS for Detection of Vulnerable Plaque by Optical Frequency Domain Imaging
Authors: Masataka Nakano, Kazuyuki Yahagi, Hirosada Yamamoto, Masanori Taniwaki, Fumiyuki Otsuka, Elena R. Ladich, Michael Joner, Renu Virmani
Journal: JACC. Cardiovascular imaging (2016)