tbuckley/cabot-search huggingface dataset:
Abstract 18164: The Effect of Sex Chromosomes on Myocardial Ischemia/Reperfusiong Injury
Authors: Jingyuan Li, Rebecca McClusky, Xuqi Chen, Arthur P. Arnold, Mansoureh Eghbali
Journal: Circulation (2013)

Introduction: Sex differences in susceptibility to ischemia/reperfusion(I/R) injury have been demonstrated both in basic and clinical settings. Female hearts show better functional recovery after I/R injury compared with males. Most of these sex differences in I/R settings have been attributed to sex hormones. Here we used two unique mouse models (four core genotypes mice and XY* mice) to investigate the role of sex chromosomes on cardiac I/R injury. Methods: We used two unique mouse models of “four core genotypes” (FCG) (XX mice with ovaries or testes and XY mice with ovaries and testes) and XY* (mice with one X chromosome (XO or XY) or with two X chromosomes (XX or XXY). All mice were gonadectomized at day75 and used 30 days after gonadectomy to eliminate the effects of gonadal hormones. Isolated hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion to measure heart function and infarct size. There were 4-7 mice per group. Two way ANOVA was used for statistical analysis. P&lt;0.05 was considered statistically significant. Values are expressed as mean± SE. Results: In both FCG and XY* models, the cardiac function was similar among all groups before ischemia. However postischemic function of XX mice was significantly lower than XY, irrespective of gonadal sex (recovery of rate pressure product (RPP): 31.2±5.7% in XX females and 44.7±8.8% in XX males vs. 56.6±5.8% in XY females and 67.2±10.1% in XY males, p&lt;0.01). Infarct size was also markedly larger in XX mice than XY (52.4±4.7% in female-XX and 49.4±7.6% in male-XX vs. 33.2±5.6% in female-XY and 30.5±5.5% in male-XY, p&lt;0.05). In XY* mice, functional recovery of mice with two copies of the X chromosome was significantly lower than mice with a single copy(recovery of RPP=34.0±10.3% XX females and 28.0±12.1% in XXY males vs. 60.3±13.5% in XO females and 60.5±13.8% in XO males, p&lt;0.05). Infarct size was also markedly larger in mice with two X chromosomes (41.4±8.9% in XX females and 46.3±9.5% in XXY males) than mice with one X chromosome (23.7±3.9% in XO females and 26.6±6.9% in XO males, p&lt;0.05). Conclusion: Irrespective of gonadal sex, the number of X chromosomes in gonadectomized mice plays a key role in susceptibility to myocardial I/R injury regardless of the presence or absence of the Y chromosome.
Patterns of locoregional failure following radiotherapy for breast cancer.
Authors: S. A. Chen, I. R. Crocker, T. Fox, T. Liu, D. Whitaker, K. D. Godette, M. A. Torres
Journal: Journal of Clinical Oncology (2011)

118 Background: To determine the influence of radiotherapy (XRT) technique on local control in breast cancer (BRCA) patients, we evaluated the relationship between PET/CT-identified locoregional recurrences (LRR) and prior definitive XRT treatment plans. Methods: Twenty-two consecutive LRRs of BRCA were identified by PET/CT in 19 patients treated from 2004-2011 with definitive post-operative radiation for their BRCA. PET/CT and original XRT CT simulation images were fused using a B-spline deformable registration algorithm (VelocityAI, Velocity Medical Solutions, Atlanta, GA) to correct for posture and soft tissue changes. Prior XRT dose to the FDG avid LRR region was calculated. LRR was classified as in-field, marginal or out-of-field. In-field LRRs were defined as ≥95% of the LRR volume receiving ≥95% of the prescribed dose (45–50.4 Gy). Marginal misses were LRRs at the field edge and/or not receiving ≥95% of the prescribed dose. Out-of-field LRRs were LRRs intentionally not treated with the original XRT plan. Results: Four LRRs were in-field, 8 were marginal and 10 were out-of-field, with two patients having both in-field and out-of-field LRRs and one having a marginal and out-of-field LRRs. Three in-field, 3 marginal and 6 out-of-field LRRs occurred simultaneously with distant metastasis (DM). In-field LRRs received a median dose of 48.4Gy (range 45-50Gy). Two in-field LRRs were marginal misses of the additional 15 Gy boost dose (median dose received 53.5 Gy); both patients had high grade, ER/PR-, and HER2 + tumors. In the 7 patients with triple negative tumors, there were 4 marginal, 4 out-of-field, and no in-field LRRs. Among marginal LRRs, a median dose of 33Gy (range 2–45.6Gy) was delivered. Out-of-field LRRs occurred in 5 supraclavicular and 5 internal mammary lymph nodes. With a median follow-up period of 3.7 yrs, the 5-yr disease-free survival (DFS) in patients with an isolated LRR is 55.6%, while in those recurring with DM, the DFS is 22.5%. Conclusions: Our study is one of the first to systematically evaluate the influence of XRT technique over local control in BRCA. Due to the number of marginal and out-of-field LRRs, our data suggest that XRT field design and dose are important factors in preventing LRRs in addition to tumor biology.
Tragedy's legacy.
Authors: Joe Brierley, Phil McShane, P. David Adelson
Journal: New England Journal of Medicine (2013)

Accidental deaths of children that are caused by superficially benign objects such as passenger cars, curtain cords, and even peanuts are subject to risk-reduction legislation. But deaths of children from gunshot wounds are different. Guns are designed to be lethal — death is not some unfortunate complication. The United Kingdom and the United States have both suffered horrific school massacres, leading people to seek both explanations and preventive legislation. However, deliberation over laws limiting access to guns ought to focus on the background prevalence of gunshot wounds among children rather than exceptional events. We compared information from a database of pediatric intensive care units in the United Kingdom (2004 through 2011) with a data set regarding traumatic brain injury in the United States (1988 through 1999). We found that in the United Kingdom, of 167,000 children admitted to the hospital, 11 had gunshot wounds and 3 died, whereas in the United States, of 98,203 children admitted to the hospital, 7.7% had gunshot wounds and more than 5000 died. Despite differences between the data-set populations (all critically ill patients 16 years of age or younger with any type of injury in the United Kingdom vs. all patients 21 years of age or younger with traumatic brain injury for whom discharge codes were recorded at U.S. centers), the fact that the total U.K. population is less than one fifth the size of the U.S. population, and the omission of data regarding prehospital deaths, there are noteworthy differences: 1.4 hospital admissions for gunshot wounds per year (in the United Kingdom) versus 1.9 per day (in the United States), and an average interval between deaths from gunshot wounds of 2 to 3 years versus 18 hours. The level of access to firearms correlates with the rate of deaths from gunshot wounds both internationally and among U.S. states. No other cause of sudden death in children would be tolerated without analysis and regulation to mitigate it. 1 Thompson, T, Kane, RR, Hager, MH. Food Allergen Labeling and Consumer Protection Act of 2004 in effect. J Am Diet Assoc 2006;106:1742-1744 2 UK Paediatric Intensive Care Audit Network home page (http://www.picanet.org.uk). 3 Tilford, JM, Aitken, ME, Anand, KJS, et al. Hospitalizations for critically ill children with traumatic brain injuries: a longitudinal analysis. Crit Care Med 2005;33:2074-2081 4 Hemenway, D, Miller, M. Firearm availability and homicide rates across 26 high-income countries. J Trauma 2000;49:985-988e 5 Miller, M, Azrael, D, Hemenway, D. Firearm availability and unintentional firearm deaths, suicide, and homicide among 5-14 year olds. J Trauma 2002;52:267-274 Language: en
Outside-In Signaling of Soluble and Solid-Phase Fibrinogen Through Integrin ΙΙbβ3 Is Different and Cooperative With Each Other in a Megakaryoblastic Leukemia Cell Line, CMK
Authors: Yumi Tohyama, Kaoru Tohyama, Misao Tsubokawa, Momoyo Asahi, Yataro Yoshida, Hirohei Yamamura
Journal: Blood (1998)
Antibodies to Various Herpesviruses in Sera From Patients With Sarcoidosis&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: B Wahren, E Carlens, A Espmark, H Lundbeck, S Löfgren, E Madar, G Henle, W Henle
Journal: JNCI Journal of the National Cancer Institute (1971)

Sera from 90 patients with sarcoidosis were examined For antibodies to Epstein-Barr virus (EBY)-associated antigens [viral capsid antigens (VCA) and early antigens (EA)] and for antibodies against a variety of other viral antigens including herpes simplex, varicella, and cytomegalovirus (CMV) antigens. Antibody titers against VCA were, on the average, 3 times higher in sarcoidosis patients than in age-matched control groups. In sarcoidosis patients, 98% were positive against 85.5% in the controls. The differences were statistically significant both with respect to titer levels and rates of positivity. Twenty-one sera which had high titers (≥160) of antibodies to VCA were also examined for antibodies to early antigens; low titers were found in 7 sera. Heterophil antibodies, also in low titers, were found in 8 of 90 sarcoidosis patients. The rates of antibodies to herpes simplex and CMV were also significantly higher among the sarcoidosis patients than in the control groups, whereas tests for other antibodies were on the same level as in the control materials. The EBV-associated VCA was demonstrated in 5 of 13 cultures derived from explanted sarcoid lymph nodes. The findings do not provide evidence of an etiologic role of EBV in sarcoidosis. The moderately elevated titers of antibodies against EBV, CMV, and herpes simplex antigens may be due to nonspecific factors like increased reactivity to certain antigens or an increased susceptibility to the respective infections or a higher tendency for recurrences of latent infections.
Heregulin regulates the actin cytoskeleton and promotes invasiveproperties in breast cancer cell lines
Authors: Mai M. Hijazi, Erik W. Thompson, Careen Tang, Peter Coopman, Jeffrey A. Torri, Dajun Yang, Susette C. Mueller, Ruth Lupu
Journal: Cancer Research (1999)

The metastatic process requires changes in tumor celladhesion proerties, cell motility and remodeling of the extracellularmatrix. The erbB2 protooncogene is overexpressed in approximately 30percent of breast cancers and is a major prognostic parameter whenpresent in invasive disease. However, it is expressed more often innon-invasive tumors, where it has no prognostic significance, thus itsrole in promoting metastatic tumor progression is not clear. A ligand forthe erbB2 receptor has not yet been identified but it can be activated byheterodimerization with heregulin (HRG)-stimulated erbB3 and erbB4receptors. The HRGs are a family of polypeptide growth factors that havebeen shown to play a role in embryogenesis, tumor formation and growthand differentiation of breast cancer cells. The erbB3 and erbB4 receptorsare involved in transregulation of erbB2 signaling, however theirrespective contributions to the progression of breast cancer have not yetbeen determined. The work presented here suggests additional biologicalroles for HRG including regulation of the actin cytoskeleton andinduction of motility and invasion in breast cancer cells. HRG-expressingbreast cancer cell lines are characterized by low erbB receptor levelsand a high invasive and metastatic index, while those which overexpresserbB2 demonstrate minimal invasive potential in vitro and arenon-tumorigenic in vivo. Treatment of the highly tumorigenic andmetastatic HRG-expressing breast cancer cell linemore » MDA-MB-231 with anHRG-neutralizing antibody significantly inhibited proliferation inculture and motility in the Boyden chamber assay. Addition of exogenousHRG ligand to non-invasive erbB2 overexpressing cells (SKBr-3) at lowconcentrations (0.2ng/ml) induced formation of pseudopodia, enhancedphagocytic activity and increased chemomigration and invasion in theBoyden chamber assay. The specificity of the chemomigration response toHRG is demonstrated by inhibition with the anti-HRG neutralizingantibody. These results suggest that HRG can act either as an autocrineor paracrine ligand to promote the invasive behavior of breast cancercells in vitro or thus may enhance the metastatic process invivo.« less
A phase I/II trial of the combination of bevacizumab, oxaliplatin, and sorafenib in patients with metastatic melanoma
Authors: E. F. McClay, A. Bessudo, L. Frakes, S. Eisenberg, R. Just, P. Banerjee, J. Sinclair
Journal: Journal of Clinical Oncology (2008)

20020 Background: Recent studies have demonstrated the importance of angiogenesis and the Ras/raf pathway in the progression of malignant melanoma. With the recent approval of several agents that target these pathways, we are now in the position to test various novel combinations in patients with metastatic melanoma. Bevacizumab blocks circulating VEGF, sorafenib also blocks the VEGF pathway but importantly it can also antagonize the RAS/Raf pathway and block the PDGF pathway providing pro-apoptotic signals. Oxaliplatin may have direct cytotoxic effect on melanoma cells. We hypothesize that the concurrent antagonism of these pathways with this combination will result in an increase in the overall response rate and in the overall survival of patients with metastatic melanoma. Methods: The purpose of this study is to determine the maximum tolerated dose of sorafenib in combination with a fixed dose of bevacizumab and oxaliplatin as well as the effects of the combination on the response rate and survival of patients with metastatic melanoma. Eligibility includes patients with measurable metastatic disease that is not surgically curable. Patients must have an ECOG PS of 0–2, adequate bone marrow, renal and hepatic function and the ability to give informed consent. RECIST criteria are employed to determine response. During the phase I portion of the study bevacizumab is administered at a dose of 5 mg/kg IV and oxaliplatin is administered at a dose of 85 mg/m2 IV every 2 weeks. These doses remain fixed for the entire study. The initial dose of sorafenib is 200 mg/day and is escalated in groups of 3 patients by 200 mg/day. Response evaluation occurs after the 3rd cycle of treatment and every 3 cycles thereafter. Results: As of January, 2008 we have entered 6 patients on this trial at the initial sorafenib dose of 200 mg. The first patient entered on the trial experienced Grade IV diarrhea, prompting the additional 3 entered patients at this dose. No further Grade III/IV toxicities have been encountered. One patient has demonstrated a partial response; two patients have had a mixed response while 3 patients have experienced progression of their disease. Conclusions: Accrual to this study will continue and we will escalate the sorafenib dose to 400 mg/day with the next patient. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Bayer
Phase I study of the novel fully human monoclonal antibody MT201, directed against epithelial cellular adhesion molecule (Ep-CAM), in patients with hormone-refractory prostate cancer (HRPC)
Authors: M. Peters, A. Dasilva, D. Weckermann, R. Oberneder, B. Ebner, P. Kirchinger, A. Fetter, R. Köhne-Volland, P. Baeuerle, P. Gjorstrup
Journal: Journal of Clinical Oncology (2004)

2600 Background: MT201 is a novel, fully human IgG1 monoclonal antibody directed against human epithelial cellular adhesion molecule (Ep-CAM), which is expressed on a wide variety of tumor cells. For breast cancer, it has been shown that high expression levels of Ep-CAM on tumor samples correlates with reduced disease-free and overall survival. MT201 has an intermediate affinity towards the Ep-CAM antigen (1.4 x 10–7 M). A wide variety of tumor cell lines are killed by MT201-mediated antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Moreover, primary prostate and ovarian cancer cells were killed by MT201 using either exogenous peripheral blood mononuclear cells (PBMCs) as effector cells or endogenous effector cells present in the tumor cell homogenate. Methods: Twenty patients were treated in a dose-escalation phase I study with two separate infusions of MT201 on study days 1 and 15 and were followed for 42 days. Doses ranged from 10 mg/m2 to 262 mg/m2. Tolerability, maximum tolerated dose (MTD), and pharmacokinetics were endpoints. Results: MT201 was generally well tolerated at all doses tested. A total of 120 adverse events regardless of relationship with study drug were reported in 19 (95%) patients during the treatment and the 28-day safety follow-up period. Most were mild or moderate, none was severe or treatment-limiting. No dose-limiting toxicities were reported and the MTD was not determined. No antibodies against MT201 were detected. A long half-life of 15 days was observed. Conclusions: MT201 might represent a new treatment opportunity for patients with epithelial cancers that overexpress Ep-CAM. Due to its favourable safety profile, the compound might be suitable even for patients at early stages in their tumor development. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Micromet AG
Phase II study of bavituximab plus paclitaxel and carboplatin in untreated locally advanced or metastatic non-small cell lung cancer: Interim results.
Authors: R. Digumarti, A. V. Suresh, G. S. Bhattacharyya, L. Dasappa, J. Shan
Journal: Journal of Clinical Oncology (2010)

7589 Background: Bavituximab, a novel chimeric IgG1 monoclonal antibody which targets the membrane phospholipid, phosphatidylserine complexed with β2-glycoprotein I on tumor vasculature, was tested in combination with paclitaxel and carboplatin in a multicenter open label, phase II trial to examine the clinical response rate and safety in adults (n = 49) with untreated locally advanced or metastatic non-small cell lung cancer. Methods: Subjects received intravenous administration of weekly doses of 3 mg/kg bavituximab until disease progression and up to 6 cycles of carboplatin at a dose of AUC = 5 and paclitaxel 175mg/m2 on day 1 of 21-day cycles in a Simon 2-stage design. Tumor response was determined by use of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: 49 Asian (India) subjects, median age 55 yrs, range 33-72, 71% male were treated. Overall response rate (CR+PR) seen in the initial group of subjects was 11/21 (52.4%, 95% C.I. 29.8-74.3) with clinical complete response in 4.8% and partial response in 47.6%. To date, median progression free survival (PFS) in the initial 21 treated is 6.2 mos (95% CI, 5.2-7.7); median duration of response and median overall survival are pending as follow-up is continuing. AEs have been reported by 44/49 (89.8%) treated subjects with the majority mild or moderate in severity. The 6 most common AEs have been pyrexia (28.6%), diarrhea (26.5%), alopecia (26.5%), anemia (22.4%), neuropathy (20.4%) and pain (20.4%). Safety analysis revealed 45 SAEs in 19 subjects (incl. 2 deaths due to myocardial infarctions and one death due to hemoptysis in 1 of 8 subjects with squamous histology). Accrual of squamous cell carcinoma was discontinued. Conclusions: Bavituximab a unique phosphatidylserine targeting monoclonal antibody which induces immune enhancement (He, et al., Clin Cancer Res 2009) and immune cell-mediated destruction of tumor vasculature appears to be safe and well tolerated when given in combination with paclitaxel and carboplatin and has produced a promising 52% overall response rate using RECIST criteria in an initial group of patients with locally advanced or metastatic non-small cell lung cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Peregrine Pharmaceuticals Peregrine Pharmaceuticals Peregrine Pharmaceuticals Peregrine Pharmaceuticals Peregrine Pharmaceuticals
A phase II study evaluating the clinical efficacy of TG4010 (MVA-MUC1-IL2) in association with chemotherapy in patients with non small cell lung cancer
Authors: T. Velu, R. Ramlau, E. Quoix, M. Pawlicki, M. Pless, H. Lena, E. Lévy, M. Krzakowski, J.-M. Limacher, N. Bizouarne
Journal: Journal of Clinical Oncology (2005)

7132 Background: TG4010 is a recombinant viral vector expressing both IL2 and the tumor-associated antigen MUC1. This vector is based on the Modified Virus of Ankara (MVA), a vaccinia virus strain significantly attenuated. A Phase II study in which TG4010 is assessed alone or in combination with chemotherapy in NSCLC patients has now completed enrolment. Methods: A multi-center randomized, two stage Simon design, two arm, phase II study in stage IIIB/IV NSCLC is described. Arm 1: TG4010 is combined upfront with cisplatin (100 mg/m2 J1) and vinorelbine (25 mg/m2 J1&J8). Arm 2: patients are treated with TG4010 alone, followed by TG4010 + cisplatin and vinorelbine upon disease progression. Response rate (RR) is evaluated according to the RECIST criteria. Median time to progression (TTP) and median overall survival (OS) was calculated according to the method of Kaplan-Meier. Results: 65 patients (15 stage IIIb - 50 stage IV) have been enrolled. In arm 1, a partial response (PR) is observed in 13/35 patients (37%) (8 so far validated by independent central review). Disease control at 12 weeks is observed in 24/35 patients (68%). In arm 2, two patients have experienced a stable disease for more than six months with TG4010 alone (up to 211 days), and, in the subsequent combination with chemotherapy, a PR is observed in 3 out of 14 patients. Arm 2 did not meet the criteria for moving forward to second stage. The median TTP for arm 1 is 6.4 [4.1–7.1] months. The intent-to-treat median OS for the whole study population is presently 13.0 [9.6–15.4] months with a 12 month survival rate of 55% [39–70]. A MUC1-specific cellular immune response was observed in lymphocyte samples from all evaluable PR patients. TG4010 is well tolerated, injection site reaction being the most frequent study drug related adverse event. Conclusions: The combination of TG4010 with standard chemotherapy shows encouraging results. Additional studies are under consideration. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Transgene S.A.