tbuckley/cabot-search huggingface dataset:
Vismodegib in the treatment of patients with metastatic basal cell carcinoma (mBCC) and distant metastases: Survival in the pivotal phase II and phase I studies.
Authors: Karl D. Lewis, Aleksandar Sekulic, Axel Hauschild, Michael Robert Migden, Anthony E. Oro, Patricia LoRusso, Charles M. Rudin, Luc Dirix, James A. Solomon, John D. Hainsworth, Sarah Williams, Jeannie Hou, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2014)

9012 Background: mBCC is rare and poorly characterized. Recent data (McCusker, in press, Eur J Cancer) indicated that between 1981-2011, the median overall survival (OS) of patients (pts) with mBCC and distant metastases was 2.0 years (95% CI 1–2.9) from time of diagnosis, with a 1-year survival probability of 58.6% (95% CI 44.6–72.6). Vismodegib (VISMO) is a first in-class Hedgehog pathway inhibitor approved for adults with mBCC or locally advanced BCC that is inoperable. Here we report OS in a pooled aBCC population of pts with distant metastases from the pivotal phase II and phase I studies in the context of survival estimates from the literature. Methods: 45 mBCC pts with radiographically measurable distant metastases, present at any site, including soft tissue, other than or in addition to regional lymph nodes, were enrolled in the phase I (NCT00607724; Von Hoff, 2009; n=16) and pivotal phase II (NCT00833417; Sekulic, 2012; n=29) trials. Pts received VISMO 150/270/540 mg/d in the phase I and 150 mg/d in the pivotal phase II trials until disease progression/intolerable toxicity. Analysis of OS in mBCC pts with distant metastases was performed 26 Nov 2013 after primary analysis for the phase I (28 Feb 2009) and the pivotal phase II (26 Nov 2010) trials. OS probability and median OS were estimated with 95% CIs by the Kaplan-Meier method. Results: The clinical characteristics of these 45 pts treated with VISMO were similar to those in the McCusker review, including mean age at mBCC diagnosis (58 yrs vs 58.5 yrs), male predominance (72% vs 80%), and mean time from initial BCC diagnosis to detection of metastases (6.3 yrs vs 7.4 yrs). 22 of 45 pts (49%) with mBCC and distant metastases who were treated with VISMO were alive at the last assessment. VISMO therapy resulted in a median OS of 2.8 yrs (95% CI 2.0–not estimable) from first dose of VISMO (vs 2.0 yrs [95% CI 1.0–2.9] in the McCusker review), and 1- and 2-year survival estimates of 84.4 % (95% CI 73.9%–95.0%) and 68.0 (95% CI 54.2%–81.9%), respectively. Conclusions: Survival of these 45 pts with mBCC and distant metastases compares favorably to historical reports. VISMO may improve OS of mBCC pts with distant metastases. Clinical trial information: NCT00833417.
Abstract 14157: Direct Renin Inhibitor Strongly Prevents Ventricular Arrhythmogenic Remodeling and Sudden Cardiac Death in Mice with Dilated Cardiomyopathy
Authors: Chinatsu Yamada, Koichiro Kuwahara, Hideyuki Kinoshita, Yoshihiro Kuwabara, Takeya Minami, Kazuhiro Nakao, Shinji Yasuno, Yasuaki Nakagawa, Kenji Ueshima, Kazuwa Nakao
Journal: Circulation (2012)

Background Progression of left ventricular (LV) remodeling including fibrosis contributes to the occurrence of lethal ventricular arrhythmias and sudden cardiac death. Hypothesis Renin-angiotensin ...
Cardiotrophin-1 protects the human myocardium from ischemic injury Comparison with the first and second window of protection by ischemic preconditioning
Authors: S Ghosh
Journal: Cardiovascular Research (2000)

Background: There are reports suggesting that cardiotrophin 1 (CT-1) is cytoprotective. We investigated the cardioprotective effects of CT-1 on the human myocardium and compared this benefit with the early and delayed protection afforded by ischemic preconditioning (PC). Methods: Right atrium specimens were prepared and incubated in buffer solution at 37°C for 30 min stabilisation, before entering one of the three following studies. In study 1, muscles (n = 6/group) were allocated to one of four groups: (i) aerobic control — incubated in oxygenated media for 210 min, (ii) ischemia alone — 90 min ischemia followed by 120 min reoxygenation, (iii) PC by 5 min ischemia–5 min reoxygenation before 90 min ischemia–120 min reoxygenation and (iv) CT-1 (1 nM) — 90 min ischemia–120 min reoxygenation with exposure to CT-1 throughout the protocol. In study 2, muscles (n = 6/group) were allocated to one of four protocols as in study 1with the exception that were incubated for 24 h followed by 30 or 90 min ischemia–120 min reoxygenation on day 2. In study 3, the same groups were employed as in study 2 with the exception that only a 30-min period of ischemia was used and that CT-1 antibody (5 μg/ml) was added to all groups throughout the experimental protocol. Creatine kinase (CK, U/g wet wt.) leakage into the medium and MTT reduction (OD/mg wet wt.), an index of cell viability, were assessed at the end of the experiment. Results: In study 1, a first window of cardioprotection was observed with PC (CK=4.39±0.34; MTT=0.58±0.03 vs. CK=7.11±0.4;MTT=0.32±0.02 in the ischemic alone group; P<0.001) but not with CT-1(CK=6.65±0.67; MTT=0.31±0.03, P = NS vs. ischemia alone). In study 2, PC applied on day 1 was protective against 30-min ischemia (CK=3.28±0.43; MTT=0.68±0.046, P<0.001 vs. ischemia alone) but not against 90-min ischemia (CK=7.13±0.66; MTT=0.24±0.03, P = NS vs. ischemia alone) induced on day 2 (second window). However, when the tissue was exposed to CT-1 for 24 h, protection was similar to that of PC when subjected to 30 min of ischemia (CK=2.95±0.71; MTT=0.77±0.05, P = NS vs. PC) and greater than PC when subjected to 90 min of ischemia (CK=4.56±0.51; MTT=0.39±0.03, P = 0.002 vs. PC). In study 3, the CT-1 antibody did not affect the protection induced by PC (CK=3.36±0.6; MTT=0.69±0.06) but it abolished the protection obtained with CT-1(CK=5.15±0.81; MTT=0.42±0.06, P = NS vs. ischemia alone group). Conclusions: CT-1 exhibits a significant protection of the human myocardium against ischemic injury when tissue is exposed to this factor for a long period (e.g. 24 h) but not when exposed for a short period (e.g. 2 h). In addition, the protection afforded by long exposure to CT-1 is as potent or even greater than the one obtained by the second window of PC. The protection induced by CT-1 but not that induced by PC can be abolished by CT-1 antibody suggesting that their beneficial action is attained by different mechanisms.
Abstract 12277: Differences in Prevalence of Peripheral Vascular Disease: An age-sex interaction
Authors: Nazir Savji, Caron B Rockman, Adam Skolnick, Harmony Reynolds, Yu Guo, Mark A Adelman, Thomas Riles, Jeffrey S Berger
Journal: Circulation (2012)

Background:  Increased chronological age is a well-known risk factor for peripheral vascular disease (PVD). Whether the relationship between age and PVD differs by sex in different vascular territories remains uncertain.   Methods:  We analyzed data from 3.6 million participants (2.3 million women and 1.3 million men) between 40-100 years of age (mean of 64.1) who underwent PVD screening in the Life Line Screening Program from 2003-2008. All subjects completed a medical and lifestyle questionnaire and were evaluated by ultrasound imaging for internal carotid artery >50% stenosis (CAS), ankle brachial indices  3cm (AAA). Association between age and outcome was identified using multivariate logistic regression analysis.   Results:  The prevalence of PVD increased with increased chronological age in both women and men ( Figure ). A significant age - sex interaction was noted for CAS (p   Conclusion:  In a self-referred screening population, the prevalence of CAS between women and men differed according to age category. Regardless of age, PAD is more common in women and AAA is more common in men. Future studies aimed at understanding these differences are needed.
VEGF, HIF-1 alpha and CD34 expressions in gastric tumors (tms): Relationship with pathological factors and prognostic impact on survival
Authors: D. Cabuk, G. Basaran, P. F. Yumuk, C. Celikel, F. Dane, M. S. Iyikesici, M. Ekenel, N. S. Turhal
Journal: Journal of Clinical Oncology (2005)

4040 Background: We planned to investigate the prognostic impact of VEGF, HIF-1alpha, CD34 in gastric cancer patients (pts). Methods: We reviewed the medical records of 51 gastric cancer pts who had total or subtotal gastrectomy at Marmara University Hospital between 1999–2004 retrospectively. We evaluated the expression of VEGF, HIF-1alpha, CD34 by immunhistochemistry in the archival tumor tissues. Cytoplasmic staining was considered as positive for VEGF. The intensity of expression is scored between 0–4+ for HIF 1 alpha. CD 34 which represents microvessel density, was scored numerically based on the intensity of staining in endothelial cells. We recorded the clinical and pathological characteristics of these patients and analyzed their survival outcome. Results: Thirty out of 51 pts were male. The median age was 63(34–81). The median follow-up was 17 months. Thirty-six pts had node positive disease. Five pts had T1, 24 pts had T2, 19 pts had T3 and 3 pts had T4 disease. Vascular and lymphatic invasion were present in 57% and 77% tumors respectively. The 5-years OS was 45% and 5-year gastric cancer specific survival was 51%. VEGF was positive in 65% of tms, HIF 1alpha was positive (from 1+ to 4+) in 71% of tms. The median CD34 staining score was 19 (3–68). In univariate analyses, the expressions of VEGF, HIF 1 alpha and CD34 were more frequent in tms without serosal invasion (p=0.018, p=0.012, p=0.003 respectively).The expression patterns of VEGF, HIF-1α, CD34 were closely linked to each other; CD34 expression was significantly more frequent in tms with VEGF and HIF-1 alpha expression (p=0.000, p=0.000). HIF-1alpha expression was more frequent in tms with VEGF expression (p=0.000). The expressions of VEGF, HIF1alpha, CD34 and other pathological characteristics were shown to have no impact on survival in the multivariate analysis. Conclusions: Angiogenesis is an early event in carcinogenesis and plays an important role in tumor growth. In line with this information, the expression of VEGF, HIF1 alpha and CD 34 were more common in tms without serosal invasion. As a future perspective, biological agents targeting VEGF, HIF1 alpha might be more effective at earlier stages of gastric cancer No significant financial relationships to disclose.
Oncogenic <i>BRAF</i> Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120
Authors: Shih-Hsun Chen, Youyan Zhang, Robert D. Van Horn, Tinggui Yin, Sean Buchanan, Vipin Yadav, Igor Mochalkin, Swee Seong Wong, Yong Gang Yue, Lysiane Huber, Ilaria Conti, James R. Henry, James J. Starling, Gregory D. Plowman, Sheng-Bin Peng
Journal: Cancer Discovery (2016)

We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490-deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer-dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive.This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer.
In Vitro Lymphocyte Dysfunction in Hodgkin's Disease
Authors: Peter R. Graze, Elliot Perlin, Ivor Royston
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article In Vitro Lymphocyte Dysfunction in Hodgkin's Disease Get access Peter R. Graze, M.D., Peter R. Graze, M.D. 2Bureau of Biologics, Food and Drug Administration, Public Health Service, U.S. Department of Health, Education, and Welfare, Bethesda, Md. 20014. Search for other works by this author on: Oxford Academic PubMed Google Scholar Elliot Perlin, M.D., Elliot Perlin, M.D. 4National Naval Medical Center, Hematology Oncology DivisiOn Bethesda, Md. 20014. Search for other works by this author on: Oxford Academic PubMed Google Scholar Ivor Royston, M.D. Ivor Royston, M.D. 2Bureau of Biologics, Food and Drug Administration, Public Health Service, U.S. Department of Health, Education, and Welfare, Bethesda, Md. 20014.5Department of Medicine, Division of Oncology, Stanford University School of Medicine, Palo Alto, Calif. 94. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 56, Issue 2, February 1976, Pages 239–245, https://doi.org/10.1093/jnci/56.2.239 Published: 01 February 1976 Article history Received: 08 April 1975 Revision received: 14 August 1975 Accepted: 04 September 1975 Published: 01 February 1976
European Lymphoma Task Force (ELTF): Report of the workshop on Mantle Cell Lymphoma (MCL)
Authors: E. Zucca, H. Stein, B. Coiffier, C. Bastard, Y. Bastion, F. Berger, G. Brittinger, P.A. Bryon, E. Callet, E. Campo, F. Cavalli, B. Coiffier, F. Dallenbach, C. De Wolf-Peeters, G. Delsol, J. Diebold, P. Felman, M. Ferrarini, J.P. Magaud, E. Montserrat, A. Norton, L. O'Brien, G. Pangalis, E. Pedrinis, S. Pileri, M.A. Pins, G. Salles, H.C. Schouten, H. Stein, S.H. Swerdlow, C. Thieblemont, D. Weisenburger, M.E. Williams, E. Zucca
Journal: Annals of Oncology (1994)
Imaging Parameters and Recurrent Cerebrovascular Events in Patients With Minor Stroke or Transient Ischemic Attack
Authors: Shadi Yaghi, Sara K. Rostanski, Amelia K. Boehme, Sheryl Martin-Schild, Alyana Samai, Brian Silver, Christina A. Blum, Mahesh V. Jayaraman, Matthew S. Siket, Muhib Khan, Karen L. Furie, Mitchell S. V. Elkind, Randolph S. Marshall, Joshua Z. Willey
Journal: JAMA Neurology (2016)

Neurological worsening and recurrent stroke contribute substantially to morbidity associated with transient ischemic attacks and strokes (TIA-S). To determine predictors of early recurrent cerebrovascular events (RCVEs) among patients with TIA-S and National Institutes of Health Stroke Scale scores of 0 to 3. A retrospective cohort study was conducted at 2 tertiary care centers (Columbia University Medical Center, New York, New York, and Tulane University Medical Center, New Orleans, Louisiana) between January 1, 2010, and December 31, 2014. All patients with neurologist-diagnosed TIA-S with a National Institutes of Health Stroke Scale score of 0 to 3 who presented to the emergency department were included. The primary outcome (adjudicated by 3 vascular neurologists) was RCVE: neurological deterioration in the absence of a medical explanation or recurrent TIA-S during hospitalization. Of the 1258 total patients, 1187 had no RCVEs and 71 had RCVEs; of this group, 750 patients (63.2%) and 39 patients (54.9%), respectively, were aged 60 years or older. There were 505 patients with TIA-S at Columbia University; 31 (6.1%) had RCVEs (15 patients had neurological deterioration only, 11 had recurrent TIA-S only, and 5 had both). The validation cohort at Tulane University consisted of 753 patients; 40 (5.3%) had RCVEs (24 patients had neurological deterioration only and 16 had both). Predictors of RCVE in multivariate models in both cohorts were infarct on neuroimaging (computed tomographic scan or diffusion-weighted imaging sequences on magnetic resonance imaging) (Columbia University: not applicable and Tulane University: odds ratio, 1.75; 95% CI, 0.82-3.74; P = .15) and large-vessel disease etiology (Columbia University: odds ratio, 6.69; 95% CI, 3.10-14.50 and Tulane University: odds ratio, 8.13; 95% CI, 3.86-17.12; P < .001). There was an increase in the percentage of patients with RCVEs when both predictors were present. When neither predictor was present, the rate of RCVE was extremely low (up to 2%). Patients with RCVEs were less likely to be discharged home in both cohorts. In patients with minor stroke, vessel imaging and perhaps neuroimaging parameters, but not clinical scores, were associated with RCVEs in 2 independent data sets. Prospective studies are needed to validate these predictors.
Abstract 199: Specific MicroRNAs Regulate Cardiac Fibroblast-to-Myofibroblast Transition And Fibrosis.
Authors: Varun Nagpal, Rahul Rai, Aaron Place, Sheila Murphy, Douglas E Vaughan
Journal: Circulation Research (2014)

Cardiac fibrosis is the pathological consequence of fibroblast-to-myofibroblast transition (FMT) within the human myocardium, resulting in heart dysfunction. Transforming growth factor-β (TGF-β) plays a pivotal role in the induction of both FMT and cardiac fibrosis. However, the molecular basis of TGF-β-induced FMT in cardiac fibrosis is not clear. In this study, we propose a novel miRNA-mediated approach to attenuate cardiac fibrosis by blocking TGF-β-induced FMT. We observed that the canonical TGF-β/SMAD pathway, and not the MEK pathway, plays a pivotal role in the induction of FMT in primary cultures of human cardiac fibroblasts. Importantly, we have demonstrated that the specific miRNA is significantly upregulated during cardiac FMT. In addition, we observed significant upregulation of the same miRNA in fibrotic human myocardium and two murine models of cardiac fibrosis (transverse aortic constriction and Angiotensin II). Furthermore, overexpression of the miRNA using mimics augmented TGF-β-induced FMT. Downregulation of the miRNA using an antagomiR approach attenuated TGF-β-induced FMT. Notably, in silico analysis and qRT-PCR analysis revealed that this miRNA directly targets apelin, an anti-fibrotic mediator. Next, efficient delivery of cy3-tagged antagomiRs in the heart, liver and spleen was confirmed by confocal microscopy. In vivo silencing of miRNAs in the heart was achieved by systemic delivery of locked nucleic acid (LNA), both in the presence and absence of Angiotensin II. We conclude that TGF-β-induced specific miRNA is both sufficient and necessary for the induction of cardiac FMT and is a novel repressor of apelin. Our data suggests that the inhibition of miRNAs necessary for FMT may serve as a novel therapeutic strategy to prevent human cardiac fibrosis.
Cocarcinogenesis Studies on Mouse Skin and Inhibition of Tumor Induction&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: B. L. van Duuren, T. Blazej, B. M. Goldschmidt, C. Katz, S. Melchionne, A. Sivak
Journal: JNCI Journal of the National Cancer Institute (1971)

Various tobacco leaf and tobacco smoke components and related synthetic compounds were tested for cocarcinogenic activity on mouse skin by simultaneous and repeated application with benzo[a]pyrene. The potent tumor-promoting agent, phorbol myristate acetate, was also tested and showed pronounced cocarcinogenic activity. Linalyl oleate and linalyl acetate showed weak cocarcinogenic activity. Linalyl laurate and the three corresponding esters of borneol showed no cocarcinogenic activity. Administration of phenol, rutin, and morin resulted in a decreased tumor yield and/or delayed tumor appearance when compared to benzo[a]pyrene administered alone.
P02 Impaired subendocardial myofibre function in primary biliary cirrhosis: Abstract P02 Table 1
Authors: I Patanwala, K Hollingsworth, J Newton, I Patanwala, R Taylor, A Blamire, D Jones
Journal: Gut (2010)

<h3>Introduction</h3> A follow-up study1 of 770 PBC patients found that their survival was much poorer than an age- and sex-matched population (standardised mortality ratio for PBC patients was 2.87). Excluding deaths from hepatic causes, the standardised mortality ratio for PBC patients was 1.73: the balance of the risk was of a cardiac-related death the mechanism by which the disease could affect cardiac tissue was unclear. 50% of PBC patients suffer systemic fatigue, and in these the risk of cardiac-related death has been shown to be higher than in non-fatigued patients.2 <h3>Method</h3> 15 proven PBC stage I–II patients were recruited (age: 48±6 y) and 8 age, weight and height- matched female subjects were recruited as controls (age: 52±11 y). MRI short axis cardiac tagging was used to measure circumferential strain and torsion throughout the cardiac cycle.3 Patient and control subject fatigue severity was assessed by means of a validated questionnaire, the Fatigue Impact Score (FIS), where 0 indicates no fatigue to a maximum of 160. Patients were divided into two groups: those without significant fatigue (defined as FIS&lt;25) and those with severe fatigue (FIS&gt;50). All controls had FIS &lt;25. <h3>Results</h3> In fatigued PBC patients, cardiac torsion was increased and circumferential strain significantly decreased compared to controls and non-fatigued PBC patients, indicating impaired subendocardial myofibre function, which is characteristic of advanced ageing.3 Anatomical MRI showed no morphological or functional alteration in the hearts of either group of PBC patients compared to controls. <h3>Conclusion</h3> In PBC patients with severe fatigue we have found changes in the relationship between peak torsion and circumferential strain indicating that these patients may have suffered effective ageing of their hearts. This is in alignment with previous findings that PBC patients with substantial fatigue had a greater risk of cardiac-related death.
Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer
Authors: Maria Teresa Herrera-Abreu, Marta Palafox, Uzma Asghar, Martín A. Rivas, Rosalind J. Cutts, Isaac Garcia-Murillas, Alex Pearson, Marta Guzman, Olga Rodriguez, Judit Grueso, Meritxell Bellet, Javier Cortés, Richard Elliott, Sunil Pancholi, Christopher J. Lord, José Baselga, Mitch Dowsett, Lesley-Ann Martin, Nicholas C. Turner, Violeta Serra
Journal: Cancer Research (2016)

Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1-S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1-CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 76(8); 2301-13. ©2016 AACR.