tbuckley/cabot-search huggingface dataset:
Abstract 3753: Critical Role of Scavenger Receptor-BI Expressing Bone Marrow-Derived Endothelial Progenitor Cells in the Attenuation of Allograft Vasculopathy by Human Apo A-I Transfer
Authors: Yingmei Feng, Miranda van Eck, Eline Van Craeyveld, Frank Jacobs, Sophie Van Linthout, Martin Erdel, Marc Tjwa, Bart De Geest
Journal: Circulation (2008)

Background: Accelerated endothelial regeneration mediated by enhanced endothelial progenitor cell (EPC) incorporation may attenuate the development of allograft vasculopathy. Hypothesis: We investigated the hypothesis that modulation of EPC biology and attenuation of allograft vasculopathy by increased HDL cholesterol following human apo A-I (AdA-I) transfer requires scavenger receptor (SR)-BI expression in bone marrow-derived EPCs. Methods: Bone marrow transplantations with SR-BI+/+ or SR-BI−/− bone marrow were performed 4 weeks before gene transfer or saline injection. E1E3E4-deleted vectors containing a hepatocyte-specific human apo A-I expression cassette or containing no expression cassette were injected via the tail vein. Two weeks later, a common carotid artery of a female Balb/c donor mouse was transplanted paratopically into male recipient C57BL/6 mice. To analyse EPC incorporation, sex mismatch bone marrow transplantations were performed in female C57BL/6 mice and incorporated EPCs were quantified by in situ hybridization for the murine Y-chromosome. Results: Following AdA-I transfer, the number of circulating EPCs increased 2.0-fold (p&lt;0.0001) at different time-points in C57BL/6 mice transplanted with SR-BI+/+ bone marrow but was unaltered in mice with SR-BI−/− bone marrow. The effect of HDL on EPC migration in vitro requires signaling via SR-BI and extracellular signal-regulated kinases (ERK) and is dependent on increased NO production in EPCs. Human apo A-I transfer 2 weeks before paratopic artery transplantation reduced intimal area at day 21 3.7-fold (p&lt;0.001) in mice with SR-BI+/+ bone marrow but had no effect in mice with SR-BI−/− bone marrow. The number of CD31 positive endothelial cells lining the lumen and the number of incorporated EPCs was increased 3.0-fold (p&lt;0.001) and 9.7-fold (p&lt;0.001), respectively, in AdA-I treated chimeric SR-BI+/+ mice compared to control mice with SR-BI+/+ bone marrow. Endothelial regeneration and EPC incorporation was not increased after AdA-I transfer in chimeric SR-BI−/−mice. Conclusion: Human apo A-I transfer-mediated endothelial regeneration to prevent allograft vasculopathy is strictly dependent on SR-BI expressing bone marrow-derived EPCs.
Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma
Authors: Wyndham H Wilson, Ryan M Young, Roland Schmitz, Yandan Yang, Stefania Pittaluga, George Wright, Chih-Jian Lih, P Mickey Williams, Arthur L Shaffer, John Gerecitano, Sven de Vos, Andre Goy, Vaishalee P Kenkre, Paul M Barr, Kristie A Blum, Andrei Shustov, Ranjana Advani, Nathan H Fowler, Julie M Vose, Rebecca L Elstrom, Thomas M Habermann, Jacqueline C Barrientos, Jesse McGreivy, Maria Fardis, Betty Y Chang, Fong Clow, Brian Munneke, Davina Moussa, Darrin M Beaupre, Louis M Staudt
Journal: Nature Medicine (2015)
22. Tumor Homing of Genetically Modified Bone Marrow Cells
Authors: Zong-Yi Li, Shaoheng Ni, Tobias Neff, Dmitry Shayakhmetovvv, Andre Lieber
Journal: Molecular Therapy (2004)

The clinical benefit of adenovirus-mediated tumor gene therapy has so far been disappointing. A potential reason for this is inaccessibility of tumor nests due to anatomical barriers formed be stromal or fibrotic tissue. The stroma immediately surrounding tumor cells consists of a three-dimensional extracellular matrix (ECM) and stromal cells such as fibroblasts and inflammatory cells and is usually well vascularized. Therefore, approaches to genetically modify (autologous) bone marrow-derived stromal cells, that after transplantation into cancer patients, home to tumor stroma appear to be promising. For example bone marrow cells could be stably transduced ex vivo to inducibly express proteases and be used as a “Trojan horse” to permeabilize the ECM for subsequent chemo- and immunotherapy as well as for treatment with oncolytic viruses. As a model to study such approaches we used SCID/NOD mice bearing liver metastases derived from MDA–MB435 human breast cancer cells. Tumor nests derived from MDA–MB435 cells are surrounded by stroma and ECM, very similar to the histopathology of ductal mammary carcinoma. In preliminary studies, we demonstrated that a significant fraction of stromal cells (mostly of macrophage lineage) surrounding the tumor nests are derived from human CD34+ cells transplanted into myeloablated NOD/SCID mice. Next we performed a similar study with genetically modified human CD34+ cells. In a first study, human umbilical cord blood-derived CD34+ cells were transduced with a RD114-pseudotyped lentivirus vector expressing GFP under the control of the EF1α promoter. Four weeks after transplantation of transduced CD34+ cells into lethally irradiated NOD-SCID mice, 40 to 50% of engrafted human cells expressed GFP in bone marrow aspirates. Eight weeks after the transplantation, mice received an intraportal transplantation of 2×106 MDA–MB435 cells. One group of mice received G–CSF injection daily to stimulate mobilization of bone marrow cells. The livers of mice were examined 3 weeks after tumor cell injection. Immunohistochemistry revealed human-derived CD45+ cells in mouse livers, specifically in the vicinity of blood vessels and around tumor nests. About 40 to 50 percent of CD45+ cells expressed GFP, indicating that transgenes can be efficiently expressed in stromal cells surrounding metastatatic tumor nests. G-CSF treatment had no effect on the recruitment of bone marrow-derived cells to the tumor stroma. Current effort are aimed towards the use of integrating, capsid-modified Adeno-AAV vectors for CD34+ cell transduction and regulated expression of metalloproteinases.
Abstract 5408: PKA and PKC Phosphorylation of Troponin I Canonical Sites Regulate Calcium Sensitivity During Force Frequency Response
Authors: Genaro A Ramirez Correa, Zhong Xin, John C Robinson, Wei D Gao, Anne M Murphy
Journal: Circulation (2008)

In failing hearts, the force-frequency response (FFR) is blunted, flat or negative. A positive FFR is crucial for healthy myocardium to respond to an increased working demand. There is no consensus in weather a positive FFR relies on myofilament Ca 2+ sensitization or desensitization and weather this is modulated by cTnI phosphorylation. In the present work we aimed to address the FFR and Ca 2+ cycling in intact mouse trabeculae loaded with Fura-2. To achieve this we used two transgenic models with pseudo phosphorylation mutants of troponin I (TnI), TnIDD 22,23 mice, which mimic increased phosphorylation at PKA sites of TnI at Ser 22 and 23 and TnI PKA/PKC mice, which mimic dephosphorylation at same PKA sites and increased phosphorylation at PKC sites of TnI at Ser 42 and 44. We hypothesized that controlling for cTnI phosphorylation will clarify the contribution of cTnI to the differences in force and Ca 2+ dynamics during FFR. When we examined the isometric contraction and Ca 2+ dynamics in each of these lines (TnIDD 22,23 , n= 8; TnI PKA/PKC, n=6) and non transgenic controls (NTG, n=7) we found that all three groups showed a positive FFR, although peak Ca 2+ increased with frequency rate in all three a less steep Ca 2+ transient increase (myofilament Ca 2+ sensitization) was observed in both transgenic lines compared to NTG (TnIDD 22,23 , p= 0.001; TnI PKA/PKC, p=0.03). Additionally, the peak force during the FFR was greater in the TnIDD 22,23 mice compared to NTG (p &lt; 0.0001), suggesting that TnIDD 22,23 mice posses an enhanced frequency rate-related myofilament Ca 2+ sensitivity. WB analysis of Ca 2+ handling proteins including PLB, pPLB, SERCA2a and Ryanodine receptor normalized levels showed no major differences among all three groups, suggesting the differences observed in TnIDD 22,23 mice were not due to altered Ca 2+ handling but rather to myofilament Ca 2+ sensitivity. We conclude that a positive systolic peak FFR is followed by increasing myofilament Ca 2+ esensitization but mimicking increased phosphorylation at PKA sites of TnI Ser 22,23 enhances FFR and Ca 2+ responsiveness. Overall, our results support the concept that myofilament alterations feedback onto Ca 2+ handling mechanisms and these findings have important implications for human heart failure.
Abstract 1205: Patients without obstructive coronary artery disease and stress test results: An analysis from the National Cardiovascular Data Registry
Authors: Manesh R Patel, Kevin J Anstrom, Eric L Eisenstein, Ralph G Brindis, Eric D Peterson, Pamela S Douglas
Journal: Circulation (2008)

Background: In stable patients without known coronary artery disease (CAD), clinical practice guidelines recommend documentation of ischemia prior to evaluation by invasive angiography. We sought to determine how often non-invasive stress testing is performed in this population and the association between stress test results and obstructive CAD. Methods: Patients undergoing cardiac catheterization for exclusion of CAD who were without prior history of myocardial infarction, PCI, or CABG were identified from 601 hospitals using the American College of Cardiology National Cardiovascular Data Registry between 2005 – 2007. Significant obstructive CAD was defined as the presence of any stenosis ≥ 50% left main or ≥ 70% major epicardial vessel. Patient demographics, risk factors, symptoms, stress test status and CAD presence were determined. Results: A total of 376,430 patients without known CAD were identified. The median age was 61 years, 53% were male, 26% had diabetes, and 69% had hypertension. At angiography, 142,912 (38%) of patients were found to have significant obstructive CAD. Symptom status was associated with the presence of CAD (stable angina 50%, atypical 25%, asymptomatic 40%; p&lt;0.001). Stress testing was performed in 316,248 (84%) of patients prior to angiography, and results were associated with the presence of CAD (p&lt;0.001) see Table . Although a positive stress test was noted in 255,617 (68% of patients undergoing cath), obstructive CAD was noted in only 105,435, yielding a positive predictive value of 41%. Conclusions: In a large national registry of stable patients without known CAD undergoing invasive angiography, only 38% were found to have significant obstructive disease. Although performed in 84% of patients prior to cath, the low positive predictive value of current stress tests may have contributed to the high rate of patients without obstructive CAD. Table p value for stress test results and presence of obstructive CAD p&lt;0.001
Abstract P6-12-04: Targeting STAT3 with novel small molecule inhibitors to sensitize breast cancer cells to radiation therapy
Authors: Lili Wang, Zhengduo Yang, Qing Xia, Haijun Chen, Guoshuai Cai, Christopher Wild, Jia Zhou, Qiang Shen
Journal: Cancer Research (2015)

Abstract Radiation therapy plays an important role in controlling the growth and progression of breast cancer. However, its efficacy is limited by the radiation-associated toxicity to normal tissue, and the intrinsic or acquired radioresistance developed in cancer cells. It was well documented that radiation onto cancer tissues cause complex changes in gene expression patterns. Thus, it may be possible to manipulate the expression of specific genes in cancer cells to increase radiosensitivity and reduce radioresistance. Accumulating studies strongly demonstrated that signal transducers and activators of transcription 3 (STAT3) is involved in cell survival, proliferation, inflammation, invasion, metastasis, angiogenesis and immune responses. Particularly, STAT3 is activated by ionizing radiation. We hypothesized that blocking STAT3 will increase sensitivity to irradiation in cancer cells. To this end, we synthesized a series of novel STAT3 inhibitors to address the challenge of radioresistance in breast cancer cells including metastatic and triple-negative lines. Among them, the compound HJC0152 and HJC0123 displayed significant inhibition of proliferation of MDA-MB-231, MCF-7 and MCF-7/Adr in dose and time dependent manners. HJC0152 and HJC0123 also induced apoptosis and necrosis in comparison to the control cells. We also found that these STAT3 inhibitors induce apoptosis of MDA-MB-231, MCF-7 and MCF-7/Adr cells by inhibiting anti-apoptotic protein Bcl-2 expression, increasing the expression of apoptotic effector protein caspase-3 and Bax. In addition, we found that HJC0152 and HJC0123 in combination with X-ray irradiation induce G2/M cell cycle arrest in MDA-MB-231, MCF-7 andMCF-7/Adr cells. The new STAT3 inhibitors increased the radiosensitivity of MDA-MB-231, MCF-7 and MCF-7/Adr cell lines, inhibited radiation-induced DNA damage repair, and promoted cells to enter mitosis, a phase more sensitive to irradiation. These changes were accompanied with decreased activation of STAT3 and decreased expression of the STAT3 downstream gene, Bcl-2. Our findings suggest that STAT3 blockade may represent an effective strategy to overcome radiation resistance, using STAT3 inhibitors as radiation sensitizers to restore the sensitivity of cancer cells to radiation therapy. Citation Format: Lili Wang, Zhengduo Yang, Qing Xia, Haijun Chen, Guoshuai Cai, Christopher Wild, Jia Zhou, Qiang Shen. Targeting STAT3 with novel small molecule inhibitors to sensitize breast cancer cells to radiation therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-12-04.
A phase I trial of an anti-pka oligonucleotide (GEM231) administered with weekly CPT-11
Authors: A. C. Lockhart, C. M. Rudin, J. D. Berlin, B. J. Roth, K. R. Hande, R. R. Martin, T. M. Sullivan, J. M. Grindel, R. Zhang, M. L. Rothenberg
Journal: Journal of Clinical Oncology (2004)

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Abstract 1318: A Mechanistic Link between High Platelet Reactivity, Inflammation Marker Release and Myonecrosis in Patients Undergoing Stenting: CLEAR PLATELETS-Ib Study
Authors: Paul Gurbel, Kevin Bliden, Tania Gesheff, Yvonne Kreutz, Udaya Tantry
Journal: Circulation (2006)

Background: Few data exist regarding the comparative effects of specific antiplatelet regimens on early inflammation marker release following stenting. The current study was performed to compare th...
Abstract 2720: “Stop telling us what to do and tell us how to do it”: A Qualitative Meta-Analysis of Skill Development in Heart Failure Self-Care
Authors: Victoria V Dickson, Barbara Riegel
Journal: Circulation (2008)

Background : Heart failure (HF) self-care requires both knowledge and skill, but little attention has been given to identifying how to improve skill in HF self-care. Methods: We assessed what self-care skills are needed and how patients develop these skills using qualitative descriptive meta-analysis techniques. Transcripts from three mixed methods studies (n=85) were re-examined and translated to yield themes about the process of developing skill in HF self-care, defined as behaviors that maintain physiologic stability (maintenance) and the response to symptoms when they occur (management). Results: The sample was 63.5% Caucasian and 58.8% male, mean age of 55.69 years (± 13.42). Most (52.9%) were NYHA class III. Narrative accounts of HF self-care revealed that the most challenging self-care maintenance skills were diet, and exercise. The management skill that was most challenging was how to titrate diuretics in response to a weight gain. Skills developed over time through coaching by trusted resources (mostly friends or family with HF). Tactical skills (“how to” prepare low salt meals; “how to” start an exercise plan) were helped by role-playing. Situational skills (“what to do when”) most essential for self-care management were evident in descriptions of how they planned for special occasions. For example, significant others helped patients think through how to manage symptoms of fluid retention while traveling. Few patients saw traditional healthcare providers as resources they could call upon to aid them in developing tactical and situational skills. Patient education was not identified as a factor associated with the development of HF self-care skill. Rather, they struggled to operationalize the self-care knowledge they attained. Conclusion: Skill in HF self-care evolves over time, with experience and practice, as patients learned how to make self-care practices fit into their daily lives, but coaching by nurses may help patients develop the skill needed to master self-care skills. Research testing coaching interventions that target skill building tactics such as role-playing in specific situations is needed.
Natural history of metastatic melanoma patients with CNS metastases
Authors: M. A. Davies, A. Y. Bedikian, S. McIntyre, T. Smith, K. Kim, W. Hwu, N. Papadopoulos, P. Hwu
Journal: Journal of Clinical Oncology (2006)

8054 Background: Melanoma has a high rate of CNS metastasis (mets). The objective of this study was to evaluate the characteristics and outcomes of melanoma patients (pts) who develop CNS mets. Methods: 333 pts with a diagnosis of CNS mets were identified from databases of 743 chemotherapy naïve metastatic melanoma (MM) pts enrolled on clinical trials between 1986 and 2004. Their clinical and pathological characteristics were reviewed. Results: The site of primary melanoma was head or neck (60/333; 18%), trunk/abdomen (144/333; 43%), limbs (66/333; 20%), ocular (2/333; 1%), or unknown (61/333; 18%). Median Breslow thickness (BT) = 2.2 mm; BT &lt; 1 mm = 39/217 (18%); and BT &lt; 2 mm = 95/217 (44%). Median Clark level (CL)= IV; CL I = 0/180 (0%); CL II = 14/180 (8%); CL III = 70/180 (39%); and CL IV = 96/180 (53%) . The median interval from diagnosis of primary melanoma to CNS mets = 29.6 (range 0.3–393) months (mos). Median survival (MS) from CNS diagnosis = 4.6 (range 0–120) mos. MS was highest for pts with brain mets (n=307; 4.8 mos) compared to pts with brain mets plus leptomeningeal disease (LMD) (14; 2.0 mos) or pts with LMD alone (11; 1.2 mos) (p=.0048 for pts with LMD vs. without). MS varied for pts with 1 (6.6 mos), 2 (4.2 mos), 3 (5.9 mos) or &gt;3 (3.5 mos) brain lesions at diagnosis of CNS mets. Among pts diagnosed with CNS mets at or prior to systemic therapy, MS was longer for pts with CNS mets only (n=20; 14.3 mos) compared to pts with CNS mets concurrent with extracranial mets (63; 7 mos) (p=.003). Patients who developed CNS mets after starting chemotherapy for extracranial mets (n=250; 3.7 mos) had a shorter MS than those diagnosed at or before systemic therapy (83; 7.9 mos, p&lt;.001). Among pts diagnosed after starting systemic therapy, CNS mets were detected ≤ 12 months from the start of chemotherapy in 30% of pts (MS = 3 mos), 12–24 mos in 37% of pts (MS = 4.6 mos), and &gt; 36 mos in 32% of pts (MS = 11.1 mos, p=.044 vs. other groups). Conclusions: This study represents one of the largest cohorts of pts with melanoma CNS mets. The presence of LMD, or development of CNS mets after starting systemic therapy, is associated with a worse prognosis. Among pts diagnosed with CNS mets at or before starting systemic therapy, the presence of concurrent non-CNS mets also portends for a worse outcome. Supported in part by Carol Courtney Memorial fund and Chiron Corporation. No significant financial relationships to disclose.
Abstract 111: In-hospital Cardiac Arrest: Predictors Of Long Term Survival After Being Discharged Alive
Authors: Wessel Keuper, Hendrik-Jan Dieker, Marc A Brouwer, Freek W Verheugt
Journal: Circulation (2007)

Background Long term survival of patients discharged alive after cardiopulmonary resuscitation (CPR) for an in-hospital cardiac arrest (IHCA) has not been extensively studied. It is also largely unknown which of these patients are at high risk for poor survival. Therefore we studied survival and predictors of survival for these patients. Methods We retrospectively studied patients who suffered from an IHCA between 1997–2004 and who survived to discharge. Data were collected using an Utstein form. A Kaplan Meier curve was calculated for survival. Survivors were compared with non-survivors and Cox regression analysis was performed to determine predictors of survival. Results In this period 222 patients had an IHCA and 19% (n=42) was discharged alive. Known predictors of survival to discharge were confirmed, primarily initial rhythm. In the discharged patients, survival after a median follow-up of 2.9 years (IQR 1.5–7.2) was 57% (n=24). Non-survivors were significantly older, median age 69.3 (IQR 59.6 –75.2) versus 56.7 (IQR 48.1– 68.8) years and had significantly more often diabetes mellitus, arrhythmias, valvular disease and cancer in their medical history than survivors. Initial rhythm did not differ between groups. After adjustment for baseline differences it was found that cancer independently predicted a lower chance of survival (HR 2.8; 95% CI 1.1–7.5). Older age tended to predict a lower chance of survival as well. Conclusion Whenever a patient is discharged alive after an IHCA, the chance of survival is evidently reduced. Only cancer independently predicted a lower chance of survival. Long term survival seems to be determined more by comorbidity than arrest variables.
Case management confers substantial benefits
Authors: T. Burns
Journal: BMJ (1996)

EDITOR,—Max Marshall claims that case management is “a dubious practice…underevaluated and ineffective…bedevilled by a tendency to lump two different approaches under one name.”1 He then bedevils it further by equating care programming with “standard” case management, and what is frequently referred to in the American literature as case management as “assertive community treatment.” In a recent editorial on the subject in the Lancet “case” and “care” were used interchangeably.2

These terms are not difficult to distinguish, and much is to be …
Abstract 5419: Hypokalemia Blunts Left Ventricular Mass Regression in Hypertensive Patients During Losartan- or Atenolol-Based Treatment: The LIFE Echo-substudy
Authors: Marcello Chinali, Gerard P Aurigemma, Peter M Okin, Eva Gerdts, Kristian Wachtell, Sverre E Kjeldsen, Stevo Julius, Björn Dahlöf, Giovanni de Simone, Richard B Devereux
Journal: Circulation (2009)

Background: It has been reported that hypokalemia (HypoK) is associated with persistent ECG left ventricular (LV) hypertrophy in treated hypertensive patients. The aim of the present study was to assess the impact of HypoK on echocardiographic LV mass regression during aggressive antihypertensive treatment. Methods: We analyzed data from 863 patients in the LIFE echo substudy (age 66±7 years, 41% women) with available serum K + levels. Patients were dichotomized according to presence of HypoK (i.e. &lt;3.90mmol/L, lowest quartile). LV mass regression after one year of treatment was compared among groups. Results: Patients with HypoK had similar mean age and gender distribution to patients with normal K + (all p=ns), but higher systolic and diastolic blood pressure (BP) and heart rate (all p&lt;0.05). After one year, similar reduction among groups in both systolic and diastolic BP (p=ns) was found. In multivariate analysis controlling for differences in age, gender, baseline LV mass, hydroclorothiazide use before or during the study, baseline BP, and BP change, patients with HypoK had a significantly lower regression of LV mass as compared to the normal K + group (p&lt;0.001). Furthermore, while in patients randomized to Losartan (n=434) reduction in LV mass was not significantly different in the absence or presence of HypoK (p=ns), in the Atenolol group HypoK was associated with a nearly 60% lower LV mass reduction (Figure ; p&lt;0.001). Conclusions: Despite similar blood pressure reduction with treatment, patients with HypoK have a lower LV mass regression. While Losartan is able to offset the negative impact of HypoK, its presence markedly affects LV mass reduction on Atenolol-based therapy. Figure. Left ventricular mass reduction after one year of anti-hypertensive treatment according to serum K + levels and treatment arm.