tbuckley/cabot-search huggingface dataset:
Endothelial Mineralocorticoid Receptor Mediates Diet-Induced Aortic Stiffness in Females
Authors: Guanghong Jia, Javad Habibi, Annayya R. Aroor, Luis A. Martinez-Lemus, Vincent G. DeMarco, Francisco I. Ramirez-Perez, Zhe Sun, Melvin R. Hayden, Gerald A. Meininger, Katelee Barrett Mueller, Iris Z. Jaffe, James R. Sowers
Journal: Circulation Research (2016)

Enhanced activation of the mineralocorticoid receptors (MRs) in cardiovascular tissues increases oxidative stress, maladaptive immune responses, and inflammation with associated functional vascular abnormalities. We previously demonstrated that consumption of a Western diet (WD) for 16 weeks results in aortic stiffening, and that these abnormalities were prevented by systemic MR blockade in female mice. However, the cell-specific role of endothelial cell MR (ECMR) in these maladaptive vascular effects has not been explored.We hypothesized that specific deletion of the ECMR would prevent WD-induced increases in endothelial sodium channel activation, reductions in bioavailable nitric oxide, increased vascular remodeling, and associated increases in vascular stiffness in females.Four-week-old female ECMR knockout and wild-type mice were fed either mouse chow or WD for 16 weeks. WD feeding resulted in aortic stiffness and endothelial dysfunction as determined in vivo by pulse wave velocity and ex vivo by atomic force microscopy, and wire and pressure myography. The WD-induced aortic stiffness was associated with enhanced endothelial sodium channel activation, attenuated endothelial nitric oxide synthase activation, increased oxidative stress, a proinflammatory immune response and fibrosis. Conversely, cell-specific ECMR deficiency prevented WD-induced aortic fibrosis and stiffness in conjunction with reductions in endothelial sodium channel activation, oxidative stress and macrophage proinflammatory polarization, restoration of endothelial nitric oxide synthase activation.Increased ECMR signaling associated with consumption of a WD plays a key role in endothelial sodium channel activation, reduced nitric oxide production, oxidative stress, and inflammation that lead to aortic remodeling and stiffness in female mice.
Neoadjuvant chemoradiotherapy (CT-RT) in patients (pts) with stage II-IVA esophageal cancer (EC): Retrospective analysis of a Spanish single institution
Authors: I. R. Quispe, B. Navalpotro, J. Capdevila, F. J. Ramos, T. Macarulla, M. E. Elez, E. Casado, J. Baselga, J. Giralt, J. Tabernero
Journal: Journal of Clinical Oncology (2008)

15635 Background: Neoadjuvant CT-RT followed by resection has been suggested to improve survival for properly selected EC pts, although the definitive role of surgery after CT-RT remains controversial. The endpoints of this study were to evaluate overall survival (OS) and pathologic complete response (pCR) rate, as well as to identify prognostic factors for OS. Methods: Pts with EC treated with CT-RT between 2002 and 2006 were identified. Treatment consisted in 3–4 cycles of cisplatin/5-fluorouracil (75 mg/m2 day 1; 750 mg/m2 CI days 1–5) with concomitant radiotherapy (total dose 50.4 Gy), followed by surgery 6 weeks after completion of CT- RT. OS was calculated using Kaplan-Meier method and multivariate analysis was done using Cox model. Results: 85 pts were studied: 79 males; median age 56 years; histology: 72% squamous cell carcinoma and 26% adenocarcinoma; baseline stage IIA 19 (22%), IIB 5 (6%), III 52 (61%) and IVA 9 (11%). After CT-RT 51 (60%) pts were resected, 39 (76%) of them showing pathological downstaging and 15 (29%) pCR. Clinical baseline and pathological staging distribution for 51 resected pts was 0= 0/17, I= 0/4, IIA= 14/13, IIB= 4/8, III= 29/8, IVA= 4/0 and IVB= 0/1, respectively. Median follow-up was 33.4 months (m). For the whole population median OS was 18.8 m and 5-year OS was 30%. Median and 5-year OS for the resected and non-resected populations were 35.2 m/40% and 11.6 m/12%, respectively. For the population resected (51 pts), those with histopathological tumor regression grade (TRG) 1–2 had an improved 5-year OS compared with those with TRG 3–5 (82% vs 13%, p<0.001); and 5-year OS was significantly higher in pts with pCR than in those without pCR (100% vs 41%, p=0.007). Multivariated analysis for the whole population identified age, clinical stage and differentiation grade as independent prognostic factors for OS. Conclusions: Our data suggest that pts with locally advanced EC may benefit with the addition of surgery after CT-RT, and the consecution of a lower TRG and/or pCR correlates with better survival. No significant financial relationships to disclose.
Cell-based immunotherapy combining encapsulation cell technology and irradiated autologous tumor cells: A novel technology platform that is both safe and feasible. Results from first in man trial
Authors: N. Mach, D. Migliorini, R. Vernet, M.-C. Belkouch, P. Luy, V. Ancrenaz, C. Py, J. Grogg, P. Harboe-Schmidt, N. Bouche
Journal: Annals of Oncology (2015)
RhesusBase PopGateway: Genome-Wide Population Genetics Atlas in Rhesus Macaque
Authors: Xiaoming Zhong, Jiguang Peng, Qing Sunny Shen, Jia-Yu Chen, Han Gao, Xuke Luan, Shouyu Yan, Xin Huang, Shi-Jian Zhang, Luying Xu, Xiuqin Zhang, Bertrand Chin-Ming Tan, Chuan-Yun Li
Journal: Molecular Biology and Evolution (2016)

Although population genetics studies have significantly accelerated the evolutionary and functional interrogations of genes and regulations, limited polymorphism data are available for rhesus macaque, the model animal closely related to human. Here, we report the first genome-wide effort to identify and visualize the population genetics profile in rhesus macaque. On the basis of the whole-genome sequencing of 31 independent macaque animals, we profiled a comprehensive polymorphism map with 46,146,548 sites. The allele frequency for each polymorphism site, the haplotype structure, as well as multiple population genetics parameters were then calculated on a genome-wide scale. We further developed a specific interface, the RhesusBase PopGateway, to facilitate the visualization of these annotations, and highlighted the applications of this highly integrative platform in clarifying the selection signatures of genes and regulations in the context of the primate evolution. Overall, the updated RhesusBase provides a comprehensive monkey population genetics framework for in-depth evolutionary studies of human biology.
Rituximab Maintenance Bimonthly for Two Years after Prolonged Immunochemotherapy in Elderly Patients with Mantle Cell Lymphoma (MCL) Results in Long Remissions: Update with Six-Year Follow-up of a Prospective Study By the Finnish Lymphoma Group
Authors: Riikka Räty, Tuomo Honkanen, Esa Jantunen, Sirkku Jyrkkiö, Marja-Liisa Karjalainen-Lindsberg, Outi Kuittinen, Minna Lehto, Maija Mikkola, Eira Poikonen, Auvo Rauhala, Johanna Rimpiläinen, Anu Räsänen, Sanna Siitonen, Merja Suominen, Mirja Vapaatalo, Erkki Elonen
Journal: Blood (2014)
Hematopoietic Engraftment of Amniotic Fluid Stem Cells Following in Utero Transplantation
Authors: Stavros P Loukogeorgakis, Enrica Bertin, Panicos Shangaris, Chiara Franzin, Aimee G Kim, Haiying Li, Martina Piccoli, Michela Pozzobon, Anna David, William Peranteau, Alan W Flake, Paolo De Coppi
Journal: Blood (2014)
A phase II clinical trial of BMS-247550 (ixabepilone), a microtubule-stabilizing agent in renal cell cancer
Authors: S. H. Zhuang, M. Menefee, H. Kotz, M. Agrawal, M. Poruchynsky, E. Hung, Z. Zhan, W. M. Linehan, S. E. Bates, T. Fojo
Journal: Journal of Clinical Oncology (2004)

4550 Background: No chemotherapy has been proven effective in renal cell cancer (RCC). The epothilones are a new generation of potent microtubule-stabilizing agents that are not P-glycoprotein substrates and active in taxane-resistant cells. We conducted a phase II trial of BMS-247550, an epothilone B analogue in metastatic RCC. Methods: Patients with metastatic RCC received BMS-247550 (6 mg/m2/day), daily for 5 consecutive days every 3 weeks. All patients had been previously treated with, been ineligible for, or refused IL-2 treatment. BMS-247550 was continued until progression or unacceptable toxicities. Results: 214 cycles have been administered in 39 patients. Treatment was well tolerated. 11 patients are still on study. A PR has been confirmed in 4 patients (10%) with clear cell RCC. 5 additional patients have had minor or mixed responses. Several post-translational modifications on a-tubulin have been shown to correlate with the extent of microtubule stability. A carboxypeptidase-catalyzed removal of the C-terminal tyrosine exposing a glutamic acid as the new C-terminal residue is one such modification. Using an antibody that recognizes glutamic acid terminated a-tubulin, we showed that the level of glu-terminated tubulin provides a reliable measure of microtubule stability. Furthermore, we were able to show an increase in glu-terminated tubulin in 6 of 12 serial tumor biopsies obtained from patients treated with BMS-247550. 50–70% of sporadic clear cell carcinomas have Von Hippel-Lindau (VHL) gene abnormalities. Consistent with previous studies reporting microtubule-stabilization by wild type VHL protein, we found that sensitivity to BMS-247550 correlates with VHL protein levels in 8 clear cell RCC cell lines. Studies using paraffin-embedded tumor are ongoing to determine if clinical response to BMS-247550 in study patients correlates with VHL gene status and protein levels. Conclusions: BMS-247550 has shown some activity against RCC. Glu-terminated tubulin level is a simple and reliable surrogate for its pharmacodynamic effects. Sensitivity of clear cell RCC to BMS-247550 is associated with VHL protein levels in cultured cells. No significant financial relationships to disclose.
A phase II trial of TLN-4601 in patients with glioblastoma multiforme (GBM) at first progression.
Authors: W. P. Mason, K. Belanger, G. A. Nicholas, I. Vallieres, D. Mathieu, A. Desjardins, P. Kavan, A. M. Omuro, D. Reymond
Journal: Journal of Clinical Oncology (2010)

2094 Background: TLN-4601 is a structurally novel farnesylated dibenzodiazepinone that has demonstrated broad in vitro cytotoxicity and in vivo tumor growth inhibition. TLN-4601 exerts its antiproliferative effects by inhibition of the Ras/MAPK signaling pathway and by apoptosis induction through caspase activation. In a phase I trial, TLN-4601 was well tolerated and demonstrated early signs of antitumor activity. As the Ras/MAPK signaling pathway is activated in GBM, together with preclinical animal data showing that TLN-4601 crosses the blood brain barrier and accumulates preferentially in implanted brain tumors, this trial was conducted to determine the activity and safety profile of TLN-4601 in patients with GBM at first progression. Methods: Phase II, multicentre, single arm, open label study of TLN-4601 monotherapy in 40 patients with proven GBM at first progression. All patients received radiotherapy and temozolomide chemotherapy as initial treatment. TLN-4601 was administered at a dose of 480 mg/m2/day by continuous intravenous (CIV) administration using a portable pump linked to a central vein. Each 21-day cycle consisted of a 14-day CIV administration followed by a 7-day rest period. Radiographic response was assessed every two cycles. Results: At the planned interim analysis, twenty patients were enrolled in this trial, and 17 were evaluable for response assessment. TLN-4601 was generally safe and well tolerated. Three patients discontinued before completing their first cycle (not evaluable) and 14 patients completed at least two cycles of therapy. Four patients were taken off treatment due to an adverse event (one assessed as possibly drug related), and 16 patients were taken off treatment due to disease progression. Three of seventeen evaluable patients had clinically and radiographically stable disease at the completion of two cycles. All three progressed at the second response assessment after completion of four cycles. Analyses of RAF-1 and pERK serum biomarkers are pending. Conclusions: Although TLN-4601 can safely be administered to patients with GBM, the drug does not appear to be effective when used as a CIV monotherapy at 480 mg/m2/day in patients with GBM at first progression. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Thallion Pharmaceuticals
Race-Strain Factor Related to Hydrocarbon-Induced Mammary Cancer in Rats&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: Katherine L. Sydnor, Otfrid Butenandt, F. P. Brillantes, Charles Huggins
Journal: JNCI Journal of the National Cancer Institute (1962)

A single dose of 7,12-dimethylbenz[a]-anthracene induced multiple cancers of the mammary gland rapidly in all Sprague-Dawley female rats, whereas under identical conditions rats of the Long-Evans strain had a low incidence of mammary cancer, with long induction time, a few tumors, and occasional regression of the cancers. The results were not significantly modified hy newborn rats of one strain foster-nursed by mothers of the other strain. The difference in susceptibility of these strains to hydrocarbon-induced mammary cancer is due to an inherited variation in their endocrine constitution with varying sensitivity of the mammary gland to the carcinogenic effect of the hydrocarbon. After multiple intravenous injections of the hydrocarbon, 94 percent of Long-Evans rats developed mammary cancer. The importance of inherited strain difference was nullified by multiple strong carcinogenic stimulation.
Activity of mTOR-Inhibitor Rad001 (everolimus) in differentiated and anaplastic thyroid cancer cell lines
Authors: T. Behlendorf, W. Voigt, T. Mueller, K. Jordan, D. Arnold, H. Schmoll
Journal: Journal of Clinical Oncology (2009)

e14608 Background: Recent data suggest that aberrant activation of PIK3/AKT-pathway and mTOR are involved in the development of thyroid cancer, particularly of anaplastic (ATC) and follicular (FTC) subtype. Therefore, mTOR could be a potential treatment target in thyroid cancer. Methods: To asses the potential role of mTOR as target for the treatment of thyroid cancer, two human ATC cell lines SW1736 and 8505C, the papillary thyroid cancer (PTC) cell line BCPAP and the FTC cell line FTC133 were exposed for 96h to increasing concentrations of the mTOR inhibitor RAD001 (Everolimus, kindly provided by Novartis, Switzerland). For combination experiments 10 nM of RAD001 were combined with increasing concentrations of either doxorubicin (DOX) or cisplatin (CDDP) continuously. Cytotoxicity was measured using the sulforhodamine B assay. IC50-values were calculated with Sigma Plot (Jandel Scientific) and drug interaction was determined by the model of Drewinko. Results: The observed IC50-values of RAD001 were 1nM (FTC133), 10 nM (BCPAP), 1000 nM (SW1736) and 9400 nM (8505C). In contrast to the pronounced differences in sensitivity as assessed on the basis of IC50, a growth inhibitory effect ≥ 25 % was seen in all cell lines at a concentration of 1 nM of RAD001. IC50 for CDDP ranged from 1,3–4,8 μM and for DOX from 8–40 nM. Combination of 10 nM RAD001 with either DOX or CDDP resulted in additive drug interaction with the exception in cell line 8505C where significant synergy was found for the combination with CDDP. Conclusion: RAD001 exerted interesting preclinical activity in two differentiated thyroid cancer cell lines. Mainly additive drug interaction in thyroid cancer cell lines was observed for combinations with CDDP and DOX. Mechanistic investigations are underway and will be presented at the meeting. At least for differentiated thyroid cancer mTOR-inhibition appeared promising, further evaluation in thyroid cancer seems warranted. No significant financial relationships to disclose.
Concurrent chemoradiation therapy (CCRT) with weekly Cisplatin in locally advanced cancer cervix (LACC): Single institution experience
Authors: M. Manji, M. A. Raja, I. Kerr, I. Badawi
Journal: Journal of Clinical Oncology (2004)

5107 Background: Though CCRT is now recommended in LACC, there is no standard regime. We review our experience with use of weekly cisplatin concurrent with radiation therapy (RT) during a three-year period. Methods: All women with LACC treated by CCRT reviewed. Demographic details, symptomatology, staging (AJCC), management, and outcome data collected. All patients had external beam radiation therapy (EBRT) 4500 cGy + boost 540 cGy in 28 fractions followed by single application brachytherapy with cesium, delivering 3000 cGy to point A + parametrial boost. Chemotherapy: cisplatin 40 mg/m2 (30 mg/m2 if para aortic nodes included in RT) weekly for 5 doses starting with RT. Results: Between 1998–2000, 33 women with median age 47 (range 23–69) treated. Median menarche age 12 (range 11–16), menopausal status: 16 pre, 1 peri, and 16 post. Obstetric history: Multiparity common, median pregnancies 8 (range 2–15), median age first pregnancy 17 (range 14–26). All but 2 presented with vaginal bleeding, 14 with pelvic pain, 5 with vaginal discharge. Median symptom duration 6 months. Diagnosis by punch biopsy all patients with 32 squamous cell carcinoma, 1 poorly differentiated carcinoma. Histologic grade 2 in 18 patients, 3 in 13, and unspecified 2. Stage IB2:3, IIB:17, IIIB:11, IVA: 2. All patients had normal baseline blood count and renal function. EBRT given to pelvis alone in 23, pelvis + paraaortic nodes in 10. Three interruptions during therapy, 14 short delays. Brachytherapy in 24 patients. Chemotherapy 11 delays, 3 dose reductions. Cycles: 22 had 5, 7 had 4, and 4 had 3. Of 33 patients, 27 (82%) achieved complete remission, 6 had persistent disease. No grade 3 or 4 hematologic/renal toxicity. Ten relapsed –4 locally, 3 distant, 3 both. With median follow up of 21 months (range 4–40), 23 disease free, 6 with active disease, 4 dead due to disease progression. Conclusion: CCRT with weekly cisplatin is a well tolerated regime, easy to administer in ambulatory care setting, and results appearpromising. More patients are being recruited. No significant financial relationships to disclose.
Trastuzumab (T) plus vinorelbine (VNR) as first combination in Her-2 overexpressing patients with metastatic breast cancer
Authors: I. Glogowska, R. Sienkiewicz-Kozlowska, B. Bauer-Kosinska, S. Jaczewska, T. Pienkowski
Journal: Journal of Clinical Oncology (2004)

3165 Background: T is effective in patients (pts) with Her-2 overexpressing metastatic breast cancer(mbc), especially in combinations with cytostatics. VNR is active agent in mbc. Preclinical data suggests synergistic cytotoxic activity between T and VNR. It is retrospective analysis of tolerability and efficacy of combination weekly intravenous VNR and T in pts with Her-2 positive mbc. Methods: 15 pts treated between Jan 2003 and Dec 2003 with combination of T and VNR were analyzed. Median age was 45,5 years (35–73), median KPS 100% (70–100). Median of metastatic sites was 2 (1–4),localisations were: soft tissue in 11 pts ( 73%), bones 5 pts (33%), lymph nodes 3 pts (20%), liver 5 pts (33%), lungs 4 pts (27%), c.n.s 1pt (7%), others 2 pts(13%). Her-2 overexpression 3+ was confirmed by immunohistochemy in all pts.12 pts were anthracycline pretreated: 10pts as adjuvant, 2 pts as first line of mbc. T and VNR were administrated weekly (T: 4mg/kg initial dose, 2mg/kg maintenance, iVNR 35mg/m2). All pts were assessed for toxicities, 14 pts for tumor response. 12 pts are still under treatment. Results: The ORR was obtained in 6 pts (40%), CR-1( 7%), PR-5 (33%). Median time of treatment duration in responders is 5,5 months (2–7,5) and 5 pts are still under treatment with median time of follow up 6,5 months (mts). In 8 (53%) pts SD was observed with median time of duration response 4,5 mts (3–7). We noted 2 (13%) cases of progressive disease with mTTP 6,5mts. The main toxicities were: neutropenia G3 in 2pts and G1–2 in 12 pts with VNR dose reductions in consequence ( first from 35mg/m2 to 30mg/m2 in 14 pts-93% and second from 30mg/m2 to 25mg/m2 in 8 pts-53%), anaemia in G 3–1 pt, infections without neutropenia G3–1pt and G2–3pts, fatigue G2–2 pts, neurotoxicity G1–4 pts, hiperbilirubinemy G2–1pt. There was no cardiac toxicity. Because of toxicities 33 cycles (10%) from 317 planed cycles of VNR were omitted. Conclusions: This analysis of small group pts suggest that weekly combination of T and VNR is active in Her-2 overexpressing mbc pts in first or second line treatment after anthracycline. Toxicities are acceptable, the main toxicity is neutropenia required dose reduction. No significant financial relationships to disclose.
Abstract B54: Characterizing pathway vulnerabilities and tumor heterogeneity through signaling-associated complexes
Authors: Matthew A. Smith, Leah Clark, Richard Hall, Kate Fisher, Takeshi Yoshida, Vincent Vuaroqueaux, Heinz-Herbert Fiebig, Ann Chen, Eric B. Haura
Journal: Clinical Cancer Research (2015)

Abstract Signaling pathways controlling cellular proliferation are major targets of cancer therapeutics, however, accurate assessment of activation status of targetable signaling cascades remains a challenge. We have developed proximity ligation assay (PLA)-based methodologies to detect signaling-associated complexes for a variety of receptor tyrosine kinases, intracellular adaptors and phosphorylation events in formalin-fixed, paraffin-embedded tissues. By assessing the degree of functional association of oncogenic kinases (such as EGFR and ALK) with intracellular adaptor molecules, it is possible to characterize the activation status of targetable kinase activity and monitor variations across tissue types, within tissues and in response to perturbations. Here, we present data for a panel of PLAs using cell lines, patient specimens and patient-derived xenografts models. We show that EGFR-GRB2 PLA reflects erlotinib pharmacodynamics and has predictive capacity for response to both erlotinib and cetuximab. We demonstrate that PLA can identify alterations in multiple bypass signaling cascades associated with therapeutic escape using both in vitro models of acquired resistance and patient specimens. We observe striking intratumoral variation in abundance of signaling-associated complexes, likely reflecting influences from the tumor microenvironment and phenotypic heterogeneity. We are currently expanding our PLA panel to include emerging therapeutic targets (MET and FGFR1) and evaluating performance of these assays to characterize signaling complexes in circulating tumor cells obtained from advanced stage non-small cell lung cancer patients. Collectively, our data suggests that PLA-based methodologies can be harnessed to explore the cancer interactome and can be important tools to enable precision medicine. Citation Format: Matthew A. Smith, Leah Clark, Richard Hall, Kate Fisher, Takeshi Yoshida, Vincent Vuaroqueaux, Heinz-Herbert Fiebig, Ann Chen, Eric B. Haura. Characterizing pathway vulnerabilities and tumor heterogeneity through signaling-associated complexes. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B54.