tbuckley/cabot-search huggingface dataset:
Fibroblast growth factor pathway in renal cell carcinoma.
Authors: I. Tsimafeyeu, L. Demidov, H. Ta, E. Stepanova, N. Wynn
Journal: Journal of Clinical Oncology (2010)

4621 Background: Recent advances in the treatment of metastatic renal cell carcinoma (MRCC) have included the use of antiangiogenic agents, which target VEGF pathway. Fibroblast growth factor (FGF) receptor (R) pathway could be an independent compensatory mechanism driving angiogenesis in the setting of VEGF blockade in MRCC. Methods: Formalin-fixed, paraffin-embedded specimens of removed 100 primary tumors and 40 metastatic lymph nodes from untreated 140 RCC patients were evaluated by immunohistochemistry with FGFR1 and FGFR2 antibodies. Level of FGFR expression was compared with 40 specimens of normal human tissue of kidney (selected from the surgical diagnostic files). Significant difference among these groups was assessed by Chi Square Fisher's Exact test utilizing semi-quantitative scoring system on extent of stained cells and intensity of corresponding immunostained cells. Using an ELISA, bFGF and VEGF-A were analyzed in the sera from 38 MRCC patients during therapy with oral sunitinib 50 mg/day in 6-wk cycles. Statistical methods included Wilcoxon rank sum and signed rank tests. Results: Expression of FGFR1 was observed in 98% of primary tumors and in 82.5% of lymph node metastases. Intensity was 3+ in all cases. Nuclear expression of FGFR1 was found in 68%. FGFR2 staining was seen in 4% of primary tumors and in 5% of lymph node metastases. Expression of FGFR1 was significant lower in the normal tissue of kidney (2.5%, P<0.01); no FGFR2 expression was found. The median pre- treatment bFGF level was 4.5 pg/ml (range 1.1 – 23). The median baseline VEGF-A level was 320 pg/ml (range 170–833). There was a significant rise in plasma bFGF levels in patients with disease progression (median increase of 9.21 pg/ml, P=0.001), but a non-significant fall in patients with response or stable disease (median bFGF level of 3.90 pg/ml, P=0.2). Plasma VEGF-A level increased in patients with response (median increase of 107 pg/ml, P=0.033). There were no detectable changes in plasma VEGF-A level in patients with progressive disease (P=0.8). Conclusions: FGFR1 was highly expressed in RCC. Plasma levels of bFGF and VEGF-A are altered in MRCC patients receiving sunitinib. The increases in bFGF levels may represent biomarker of resistance to targeted therapy. No significant financial relationships to disclose.
Immunologic and Enzymatic Studies of Two Breeding Lines of NZB Mice That Differ in Chromosome Breakage&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: H Haddada, N Munsch, C de Vaux Saint Cyr, I Emerit
Journal: JNCI Journal of the National Cancer Institute (1983)

Two sublines of NZB/BI mice were developed by selective matings according to chromosome breakage frequencies. These sublines--HB, a line with high chromosome breakages, and LB, a line with low or normal breakage rates--were studied in regard to the age of the animals as it related to two different aspects. The first aspect was immunologic: A decreased response to T-cell mitogens was found in old NZB mice, but this response was more pronounced in HB mice. The response to the B-cell mitogen (lipopolysaccharide) was increased in both sublines as compared to that in BALB/c mice. The percentages of IgG-positive and theta-positive spleen cells were evaluated in both sublines: Some increase in IgG-positive cells was observed in the spleens of 2- to 8-month-old NZB mice and a slight decrease was seen after age 8 months. The percentage of theta-positive cells diminished according to the age of the mice, and the decrease occurred earlier in HB than in LB mice. The second aspect studied was enzymatic and concerned the levels of DNA alpha- and beta-polymerases and terminal DNA nucleotidyltransferase in the thymuses and spleens of these animals. The major finding noted was an augmentation of 100-200% in the terminal DNA nucleotidyltransferase levels in HB thymuses by comparison with LB thymuses. The levels of both polymerases were increased in spleen cells of HB mice as compared to those of LB mice.
Abstract 315: Mice With Cardiac-restricted Overexpression Of Myozap Are Sensitized To Biomechanical Stress And Develop A Protein-aggregate Associated Cardiomyopathy
Authors: Derk Frank, Reza Poyanmehr, Ashraf Rangrez, Christian Kuhn, Christine Grund, Werner W Franke, Norbert Frey
Journal: Circulation Research (2013)

The intercalated disc (ID) is a major component of the cell-cell contact structures of cardiomyocytes ensuring their electro-mechanical coupling. In previous work, we could identify and characterize Myozap, a novel cardiac-enriched ID protein, which interacts with several other ID proteins. We could now show in cardiomyocytes that overexpression of Myozap activates the Rho-dependent SRF pathway. Consistently, RNAi-mediated Myozap knockdown blocked Rho-mediated SRF activation linking the ID to gene regulation and actin dynamics. For further analyses of Myozap’s functions in vivo, we generated a mouse model with cardiac overexpression of Myozap cDNA (αMHC promoter). 1 year old mice developed cardiomyopathy with significant hypertrophy (heart weight/tibia length +43%, p&lt;0.01, n=8-10) as well as LV dilation (LVEDD +20%, p&lt;0.01) and a trend towards LV dysfunction (fractional shortening 50% vs. 42%, n=10, p=0.07). Consistently, these mice displayed upregulation of the hypertrophy-associated gene program (nppa 4.3-fold, p&lt;0.001, and nppb 2.2-fold, p&lt;0.01, n=7-9). On the ultrastructural level, we could detect bulky aggregates containing Myozap, desmoplakin and other ID proteins. This aggregate-associated pathology closely resembled the changes in the hearts of patients suffering from desminopathies. Interestingly, desmin was not detectable in the aggregates in MyozapTG mice, but appeared to be displaced from the ID. Further molecular analyses in the aged mice also revealed dysregulation of typical members of the unfolded protein response (UPR) associated with upregulation of UPR-related apoptosis (cleaved caspase 12). Functionally, pressure overload via transverse aortic constriction (TAC) caused exaggerated cardiac hypertrophy (heart/body weight 7.9 mg/g in Myozap TG-TAC vs. 5.6 mg/g in WT-TAC, n=11 each group, p=0.002) and loss of contractility (fractional shortening of 15.3% in Myozap TG-TAC vs. 33.0% in WT-TAC, n=11 each group, p&lt;0.001). Similarly, a physiological stimulus (voluntary running) led to a less dramatic but significant premature LV dysfunction. In conclusion, Myozap overexpression offers new insights in the pathogenesis of protein aggregate-associated cardiomyopathies.
Abstract A53: Integrative data analysis of colorectal cancer reveals the frequently metastatic sample cluster
Authors: Shingo Tsuji, Yutaka Midorikawa, Motoaki Seki, Tadatoshi Takayama, Yasuyuki Sugiyama, Hiroyuki Aburatani
Journal: Clinical Cancer Research (2015)

Abstract High-throughput biological technologies enabled to identify cancer related key molecules and subclasses. However, single experiment could only elucidate one feature of the tumor pathway. In order to identify the clusters and pathways significant for cancer progression, we performed integrated analysis using gene expression and DNA methylation profiles of colorectal cancer samples. Extracting core CpG sites from CpG island with our newly developed method, iClusterPlus, one of integrated analyses methodologies, was applied to expression array and methylation profiling data and 116 colorectal cancer samples were divided into various cluster size (2≤k≤11). We examined clusters (k=3 and k=6), and found that each cluster (k=3) clearly corresponds to three groups consisting of the combination of two clusters in cluster (k=6) with different prognosis. Expression profiles of two clusters in each group were significantly different, which suggests that aberrant DNA methylation is accumulated during the early stage of cancer, while alteration of gene expression profile is the late event of cancer progression. Furthermore, network-based analysis using expression profiles demonstrated that modules including hnRNP family was down-regulated in one of the cluster (k=6) which frequently harbored liver metastasis and poor prognosis. Integrated clustering analysis applied to multidimensional methods is available to identify disease characteristics such as survival rate and distant metastasis, which might be valuable for improving cancer therapy. Citation Format: Shingo Tsuji, Yutaka Midorikawa, Motoaki Seki, Tadatoshi Takayama, Yasuyuki Sugiyama, Hiroyuki Aburatani. Integrative data analysis of colorectal cancer reveals the frequently metastatic sample cluster. [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 A53.
Thioridazine Hydrochloride (Mellaril): Its Effect on the Electrocardiogram and a Report of Two Fatalities with Electrocardiographic Abnormalities
Authors: H G KELLY, J E FAY, S G LAVERTY
Journal: JAMA (1963)

Twenty-eight electrocardiograms are presented which depict a quinidine-like effect of thioridazine on ventricular repolarization, in doses as low as 200 mg. a day. T waves have been found to flatten out and sometimes invert. Occasionally S-T segments have become convex and U waves have appeared.Case reports are presented of two patients who died while receiving large doses of thioridazine, 1500 and 3600 mg. daily, respectively. Terminal ECG patterns in each instance were those of heart block, alternating with episodes of ventricular tachycardia.The myocardium of one of the fatal cases revealed edema, increased vascularity, and some increase in connective tissue elements, along with fragmentation of muscle fibers. These changes were most pronounced in the interventricular septum.It is concluded that, because of the quinidine-like action of thioridazine on ventricular repolarization, caution is indicated when it is administered in large doses.
Reply to Daniela Wittmann, Ted A. Skolarus’ Letter to the Editor re: Neil E. Martin, Laura Massey, Caleb Stowell, et al. Defining a Standard Set of Patient-centered Outcomes for Men with Localized Prostate Cancer. Eur Urol 2014;67:460–7
Authors: Neil E. Martin, Caleb Stowell
Journal: European Urology (2016)
The triplet vinorelbine (NVB), ifosfamide (IFO) and cisplatin (CDDP) (NIP) used as post-operative treatment versus surgery alone in patients having received primary chemotherapy (CT) for locally advanced (LA) non small cell lung cancer (NSCLC)
Authors: D. Grunenwald, G. Ziolo, H. Olechnowicz, J. Dahabreh, F. Carpagnano, S. Leong, A. Fittipaldo, C. De Almeida, D. Aubert, M. Gottfried
Journal: Journal of Clinical Oncology (2004)

7172 Background: Neo-adjuvant chemotherapy can allow resection in patients with locally advanced NSCLC. From January 1999 to December 2002, 156 patients have been enrolled in a prospective study aimed to evaluate downstaging after induction CT by NIP. Methods: Patients with IIIA; IIB (only T3N0) and IIIB (only T4N0) were eligible to enter into the study. All patients with clinical N2 had a mediastinoscopy plus biopsy or Fine Needle Aspiration (FNA) to certify the lymph node involvement. After receiving 3 cycles of NIP (NVB 25 mg/m2 d1, 5; IFO 3 g/m2 d1; MESNA 3g/m2 d1 and CDDP 80mg/m2 d1 every 3 weeks) all patients without progression or who were not withdrawn for any reason were eligible for surgery. No RT was allowed in both arms. Results: One hundred and seven patients (69%) were operated out of 155 patients treated by neoadjuvant chemotherapy. Lobectomy was possible in 54 patients (50%) and pneumonectomy was performed in 42 patients (39%). Atypical segmentectomy was performed in 1 patient (1%), explorative surgery in 6 patients (6%). Data are missing for 4 patients (4%). Complete resection rate (R0) was of 74% (79/107patients). Post-surgical downstaging was observed in 28% of the N2 patients who were completely resected. The median time to surgery was 32 days (range 21–67 days) from the last NVB administration. Peri-operative toxicity included intestinal obstruction, bronchial infection and empyema (1 patient each) and 3 patients died within 30 days after surgery (2 patients with left pneumonectomy and one with right pneumonectomy). With a median follow-up of 33 months, 16 patients (15%) with local relapse and 4 patients (4%) with supraclavicular lymph node relapse have been reported. Conclusion: The triplet combination of NIP allowed surgery in LA NSCLC without increasing either morbidity or mortality on this population. Moreover, no delay was reported between end of CT and surgery. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pierre Fabre
Phase II trial of irinotecan (CPT-11) and radiation followed by irinotecan and BCNU in glioblastoma patients (pts)
Authors: K. V. Ballman, K. A. Jaeckle, P. Schomberg, C. Giannini, E. Galanis, P. Brown, R. Arusell, J. Reid, J. Hammack, J. Buckner
Journal: Journal of Clinical Oncology (2006)

1562 Background: Prior studies have shown additive effects of CPT-11 in combination with BCNU, and radiosensitizing effects of CPT-11 in gliomas. Methods: All pts had GBM by central review prior to registration. With MTD based on a pilot study (Arm A), those not receiving anticonvulsants (non-EIAC, Arm C) received RT with concomitant CPT-11 (125 mg/M 2 /wk × 4, cycle 1), followed by BCNU (100 mg/M 2 q 6 wk) + CPT-11 (75 mg/M 2 /wk × 4, q 6 wks, cycles 2–5) beginning within 4 wks of RT. Pts on EIAC (Arm B) received CPT-11 (400 mg/M2/wk × 4, cycle 1) during RT, then post-RT BCNU (100 mg/M 2 q 6 wk) + CPT-11 (400 mg/M 2 /wk q 6 wks, cycles 2–5). Dose de-escalations (but no escalations) were allowed. Toxicity was graded by CTC v. 3.0. Primary endpoint was overall survival at 12 mo (OS12), with a interim futility analysis after 12 mos. follow up in the first 35 patients. 18 “successes” (survival &gt; 12 mo) were required to proceed. Results: There were 56 pts treated (20 Arm A, 12 Arm B, 24 Arm C). Six pts on Arm A developed toxicity at the pilot CPT-11 cycle 2–5 dose of 125mg/M2, requiring reduction (75 mg/M 2 ) for the remainder of Arm A and all Arm C pts. The decision rule for the first 35 patients was not met, with inclusion of the 6 Arm A pts (14 successes, 19 failures, 2 incomplete data) or without these pts ( 13 successes, 20 failures, 2 incomplete). In the 35 pts with mature data, the best confirmed response was PR in 2 (6%), REGR in 4 (11%) and stable (&gt;4 wks, STAB) disease in 7 (20%). For the 56 pts (51 with mature data), PR, REGR and STAB were noted in 4%, 16%, and 39% respectively. Reason for end of treatment (N=56) was: completion of study treatment (13%); pt refusal (11%); adverse event (9%); progression (39%); all cause death (9%); too early (13%) or other (7%). In the 51 pts whose data is mature, progression free survival at 6 mos (PFS6) was 29.8% (95% CI: 19.1, 46.3); PFS12 was 16.5% (95% CI: 8.3, 32.9) and OS at 12 mos was 45.4% (95% CI: 32.7, 63). Overall median survival was 10.7 mos (95% CI: 7.8, 14.5). Conclusions: Although limited activity (PR+REGR+STAB) of this combination was demonstrated, the decision rule (minimum OS12 “successes”) was not reached, and tolerability of this regimen was only moderate. We consider the regimen as not superior to results obtained with other regimens in prior NCCTG studies. No significant financial relationships to disclose.
Correlation of Ca15–3 elevation with number and site of metastasis in breast cancer patients
Authors: M. T. T. Ramirez, M. I. Vazquez Lopez, B. E. Vela, D. Flores, M. D. Uribe, M. I. Vazquez, B. E. Santinelli, I. Zeichner
Journal: Journal of Clinical Oncology (2004)

875 Background: The tumor marker ca153 has been widely used in the follow up of breast cancer patients providing a good method for early detection of relapse. The objective of our study is to correlate, if possible, the value of the marker with number and site of metastases, in order to reduce the imaging studies and cost of treatment. Methods: We reviewed the clinical laboratory ca15–3 test results from 2000 to April of 2003, and for those that were elevated above 30 u., the clinical record was obtained. Data of clinical stage, levels of ca153, number and site of metastases were recorded and analyzed with stata 7.0. Results: We included 503 patients that had at least one elevation. Of those, 307 ( 61%) presented metastasis or loco-regional recurrence and we classified them as group 1. The rest, 196 patients never developed metastasis or recurrence constituted group 2. Mean age of all the patients was 49.7 years (22–86). Maximum level for group 1 had a mean of 435.7 (30.5–4327) and for group 2 57.9 u. (30–624) with a significant difference (p=0.0000). A gradual increase was also observed in the means according to clinical stage: Stage 1: 82.6; Stage 2 491.4; stage 3: 595.8; 4: 480.5 and non classified 352.7 . The same gradual elevation was observed with positive lymph nodes: No positive nodes mean of 167.9, one to three positive nodes 270.2, four to nine 389.2, 10 and more 491.5 The number of metastasis was also important one metastasis had a mean of 255.6, two sites 412.6, three 635.6, four 759.9 and five 2061 ( p=0.000). The site of recurrence had no significant difference between soft tissues, means under 100 p=0.20. For only lung metastasis mean level was of 398.7, bones 307.8, brain 264.6, liver 309. 3. (p= 0.001) with higher values for bone and liver. Conclusions: We observed that the most significant parameters were clinical stage, nodal status, number of affected sites and higher increase with bone and liver metastasis. No significant financial relationships to disclose.
Carcinogenic Effect of Subcutaneously Administered N -Nitroso-2,6-dimethylmorpholine in Syrian Golden Hamsters 2
Authors: Jürgen Althoff, Carter Grandjean, Barry Gold
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Carcinogenic Effect of Subcutaneously Administered N-Nitroso-2,6-dimethylmorpholine in Syrian Golden Hamsters Get access Jürgen Althoff, Jürgen Althoff 3Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 42d St. and Dewey Ave., Omaha, Nebr. 68105. 4Present address: Abteilung für Experimentelle Pathologie, Medizinische Hochschule Hannover, Karl-Weichen-Allee 9, 3000 Hannover 61, Federal Republic of Germany. Search for other works by this author on: Oxford Academic PubMed Google Scholar Carter Grandjean, Carter Grandjean 3Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 42d St. and Dewey Ave., Omaha, Nebr. 68105. 5Address reprint requests to Dr. Grandjean. Search for other works by this author on: Oxford Academic PubMed Google Scholar Barry Gold Barry Gold 3Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 42d St. and Dewey Ave., Omaha, Nebr. 68105. 6We thank Jim Nielsen for GLC-MS analysis, Kathy Stepan for technical assistance, and Mardelle Susman for editorial help. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 60, Issue 1, January 1978, Pages 197–199, https://doi.org/10.1093/jnci/60.1.197 Published: 01 January 1978 Article history Received: 04 April 1977 Accepted: 20 July 1977 Published: 01 January 1978
A phase II pilot trial of low dose, continuous infusion, or “metronomic”, paclitaxel and oral celecoxib in patients with metastatic melanoma
Authors: D. F. McDermott, D. C. Cho, J. R. Merchan, R. S. Bhatt, V. Seery, J. L. Mosher, M. B. Farquhar, J. W. Mier, M. B. Atkins, V. P. Sukhatme
Journal: Journal of Clinical Oncology (2006)

8010 Background: In patients (pts) with metastatic melanoma (MM), tumor angiogenesis has been associated with tumor progression and survival (Ugurel et al, JCO 19:577). Microtubule and cyclooxygenase (COX)-2 inhibitors, both alone and in combination, have been shown to have inhibitory effects on endothelial cells and tumor angiogenesis both in vitro and in vivo (Merchan et al, Int J Ca 113:490. Jones et al, Nat Med 5:1418). We tested the safety and efficacy of a regimen involving low dose, continuous infusion (CIV) paclitaxel and oral celecoxib in pts with MM. Methods: Pts received paclitaxel 10mg/m 2 for 96 hours weekly by CIV and Celecoxib 400 mg po/bid. Systemic tumor response was assessed at 6 wk intervals (1 cycle (C)). Pts without unacceptable toxicity or clinically significant disease progression (PD) received additional cycles. Pts exhibiting PD after C 2 relative to end of C 1 were removed from study. Pts on anticoagulants, with recent MI or untreated brain metastases were ineligible. Results: 20 pts (12 M/ 8 F), median age 55 (range 44–65), ECOG PS 0/1/2 (5/13/2), M1a/M1b/M1c: 1/1/18 (90%), and prior systemic therapy regimens 0/1/2/3+: 1/7/5/7 were enrolled in the protocol. Sites of systemic disease included: lung (13 pts), LN (14), soft tissue (13), liver (9), bone (4), brain (6), other (11). 3 pts came of study prior to treatment with rapid disease progression. Treatment related grade 3–4 toxicities included line related (LR) bacteremia (3 pts), LR DVT (3 pts), LR PE (3). There were no grade 3–4 toxicities attributed to paclitaxel or celecoxib. No pt exhibited a major tumor response; 6/20 (30%) pts had stable disease for 17, 18, 18, 18+, 30+, 60 wks. Median TTP was 6 wks (range 3- 60); median overall survival was 6 months (range 1–29). Conclusions: Low-dose, CIV paclitaxel and oral celecoxib leads to disease stabilization in a significant portion of previously treated pts with MM. This suggests a role for combination anti-angiogenic therapy in MM. The incidence of LR toxicities indicates that alternative microtubule inhibitors, such as oral taxanes, should be considered in combination with COX-2 inhibitors for future studies. Results of biomarker studies will be presented at the meeting. Supported by Pfizer Inc. and NIH R21 CA097730. [Table: see text]