tbuckley/cabot-search huggingface dataset:
Next generation RNA sequencing of neuroendocrine prostate cancer.
Authors: H. Beltran, S. Terry, D. Pflueger, A. Sboner, N. Kitabayashi, S. T. Tagawa, F. Demichelis, M. B. Gerstein, D. M. Nanus, M. A. Rubin
Journal: Journal of Clinical Oncology (2010)

e15010 Background: Neuroendocrine prostate cancer (NEPC) represents a distinct, aggressive form of prostate cancer that may present de novo or following hormonal treatment of prostate adenocarcinoma (PCa). Despite aggressive chemotherapy, most patients die within a year. We used expression profiling to identify genetic alterations in NEPC and nominate therapeutic candidates. Methods: We performed massively parallel paired-end RNA sequencing (RNA-Seq) using the Illumina Genome Analyzer II. We employed a Bioinformatics approach to quantify gene expression, evaluate point mutations, and utilized a novel computational tool (FusionSeq) to identify gene fusions (archive.gersteinlab.org/proj/rnaseq/fusionseq). Connectivity Mapping (CMAP), a program to correlate expression data with gene expression of cells treated with 1309 small molecules (broadinstitute.org/cmap), was used to nominate compounds that reverse the NEPC gene signature. Results: 7 NEPCs were evaluated, with 3 being pure NEPC and 4 mixed with PCa. 65-125 million paired-end reads were obtained (52-61% mappable to reference genome). 9 highly ranked gene fusions were detected, including TMPRSS2-ERG in 1/7 cases. 28% of known genes showed significant gene expression differences compared to 51 PCa reference cases (Benjamini- Hochberg correction p <0.05). Neuroendocrine genes (CGHA, CGHB, S100) were high, androgen regulated genes (PSA, TMPRSS2, NKX3.1) and AR were low, and EZH2, MIB1, SYP were differentially expressed in NEPC versus PCa, with exception of the TMPRSS2-ERG NEPC case which showed a pattern similar to PCa. Several kinases implicated in cancer were upregulated in NEPC (AURKA, AURKB, CDK2, TYK2). CMAP nominated drug candidates, including known chemotherapeutic agents (etoposide), HDAC inhibitors (vorinostat), the red wine derivative resveratrol, and SERM raloxifene. Conclusions: RNA-Seq detected significant genetic differences between NEPC and PCa. The NEPC case that resembles PCa on a molecular level may represent a significant intermediate subtype. Ongoing RNA-Seq analysis, including pathway and mutation analyses, will help identify driving lesions. Overexpression of kinases may represent previously unknown targets for therapeutic intervention. No significant financial relationships to disclose.
Abstract 19028: Ablation of the Calpain-Targeted Site in Cardiac Myosin Binding Protein-C is Cardioprotective
Authors: David Barefield, Xiang Ji, Guangshuo Zhu, Eiki Takimoto, Pradeep K Luther, Dobromir Dobrev, David A Kass, Sakthivel Sadayappan
Journal: Circulation (2012)

Rationale: Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is essential for normal heart function. We recently demonstrated a direct correlation between cMyBP-C dephosphorylation and its degradation during ischemia-reperfusion (I-R) injury. Strikingly, cMyBP-C phosphorylation protects the heart from I-R injury. However, the mechanism of cMyBP-C-mediated cardioprotection is unknown. Objective: To determine if preventing cMyBP-C proteolysis and cleavage confers cardioprotection during I-R injury. Methods and Results: cMyBP-C is a substrate for calpain and dephosphorylation makes cMyBP-C more susceptible to proteolysis. In patients with congestive heart failure, increased calpain activity was associated with cMyBP-C degradation. During ischemia proteolysis leads to the cleavage and release of the predominant N-terminal fragment (40 kDa) in association with increased calpain activity. MS/MS analysis identified a motif in the cMyBP-C M-domain responsible for the release of the 40 kDa fragment, 272-TSLAGAGRR-280, which we term the calpain-targeted site (CTS). Next, we used cardiac-specific transgenic mice expressing an ablated CTS (cMyBP-C[[Unable to Display Character: &amp;#8710;]]CTS) which were bred into cMyBP-C null (t/t) mice. We hypothesized that ablation of the CTS would confer resistance to calpain-mediated proteolysis and protect the heart from I-R injury. An animal that transgenically expressed the normal cardiac isoform, cMyBP-CWT, served as a control. Histological, electron microscopic and immunofluorescence analyses confirm that cMyBP-C[[Unable to Display Character: &amp;#8710;]]CTS incorporates normally into the cardiac sarcomere and results in rescue of the cMyBP-Ct/t phenotype compared to control. Echocardiography and in vivo hemodynamic studies revealed that cMyBP-C[[Unable to Display Character: &amp;#8710;]]CTS mice have normal cardiac function similar to control mice. Altogether, these data suggest that cMyBP-C[[Unable to Display Character: &amp;#8710;]]CTS is benign. Compared to cMyBP-CWT, cMyBP-C[[Unable to Display Character: &amp;#8710;]]CTS protein is protected from calpain-mediated degradation. Finally, we determined that ablation of the CTS preserved cMyBP-C stability and cardiac function during I-R injury. Conclusions: Our data suggest that preserving cMyBP-C stability by thwarting calpain-mediated proteolysis protects the heart from I-R injury.
Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.
Authors: S E Rivkin, S Green, J O'Sullivan, A B Cruz, M D Abeloff, W R Jewell, J J Costanzi, W B Farrar, C K Osborne
Journal: Journal of Clinical Oncology (1996)

PURPOSE To determine whether the addition of surgical ovariectomy to standard chemotherapy prolongs disease-free survival (DFS) and overall survival in premenopausal patients with estrogen receptor (ER)-positive operable breast cancer with positive axillary nodes. PATIENTS AND METHODS Three hundred fourteen premenopausal patients with ER-positive, node-positive breast cancer were enrolled between July 1979 and July 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive either of the following: (1) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (i.v.) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 i.v. weekly for 1 year, vincristine .625 mg/m2 i.v. weekly for the first 10 weeks, and prednisone weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (2) bilateral ovariectomy followed by CMFVP. RESULTS The median follow-up time is 7.7 years and the maximum 13.2 years. Treatment arms are not significantly different with respect to either survival or DFS (one-sided log-rank, P = .55 and .70, respectively). The 7-year survival rate is 71% on the CMFVP arm and 73% on CMFVP plus ovariectomy. No significant differences were observed in node or receptor level subsets. CONCLUSION We conclude that, in this study, the addition of ovariectomy did not improve results over chemotherapy alone in the treatment of premenopausal women with node-positive, ER-positive, operable breast cancer. Our sample size was too small to detect a small improvement. The death hazards ratio of CMFVP/CMFVP plus ovariectomy was 1.22 (95% confidence interval [CI], .79 to 1.89).
Long-term outcomes among survivors of childhood central nervous system tumors: A report from the childhood cancer survivor study
Authors: G. T. Armstrong, K. Ness, J. Whitton, W. M. Leisenring, Y. Yasui, L. Zeltzer, S. Donaldson, M. Hudson, L. L. Robison, R. Packer
Journal: Journal of Clinical Oncology (2008)

10015 Background: To improve survival in childhood CNS tumors aggressive surgical intervention, radiotherapy, and chemotherapy have been employed. Long-term survivors are at risk for a broad array of late-effects secondary to tumor location and/or therapeutic interventions. Methods: Analysis included 1,538 5-yr survivors of childhood CNS tumors (including 1,035 with Astrocytoma [AST], 306 Medulloblastoma/PNET [M/PNET], 115 Ependymoma [EP], and 82 Others). Patients, diagnosed 1970–86, had a median follow-up of 22.1 yrs (range16.1–34.6). Outcomes of mortality, second malignant neoplasm (SMN), health status, education, employment, insurance, and marital status were assessed to determine risk associated with tumor type and treatment modality including region-specific cumulative radiation (RT) dose to the CNS. Results: 307 deaths >5 yrs after diagnosis resulted in a cumulative late mortality rate of 18.2% (95% confidence interval [CI] 16.1–20.3) at 25 yrs (EP 23.3%; M/PNET 19.0%; AST 17.3%). Standardized mortality ratios were 13.5 (95% CI 9.2–19.1) for EP; 13.1 (95% CI 10.2–16.6) for M/PNET; and 9.8 (95% CI 8.5–11.3) for AST. Late disease recurrence (n=188) and SMN (n=37) represented the most common causes of death. Cumulative incidence of SMN was 2.7% (95% CI 1.9–3.4) at 20 yrs. RT was associated with a two-fold risk of SMN (odds ratio [OR]=2.0, 95% CI 0.95–4.3). Adverse health status was reported by 57%. Treatment with RT or chemotherapy (vs Surgery only) was associated with an increased risk of severe impairment in general health (OR=2.8, p<0.001), functional status (OR=2.2, p<0.001), and activity level (OR=2.1, p<0.001). Exposure of >30Gy to any CNS region was associated with statistically significant (P<0.01) lower rates for educational attainment, marriage, employment, and personal income while exposure to <30Gy resulted in similar rates to non-irradiated patients for all outcomes. Conclusions: Survivors of childhood CNS experience substantial long-term adverse effects of therapy and are a high priority group for intervention strategies. No significant financial relationships to disclose.
Randomized phase II trial of carboplatin (C) and gemcitabine (G) with or without dexamethasone (Dex) in patients (pts) with stage IV non-small cell lung cancer (NSCLC).
Authors: J. J. Rinehart, S. M. Arnold, G. H. Kloecker, A. Lim, M. A. Zaydan, S. Slone, J. Croley, E. Kvale
Journal: Journal of Clinical Oncology (2010)

9150 Background: The macrophage driven innate inflammatory response to cancer, as reflected by elevated C-reactive protein (CRP) and hypo-albuminemia, adversely effects treatment toxicity and efficacy. Our pre-clinical studies suggest that Dex given 4 days before and the day of chemotherapy reduces hematologic toxicity (tox) and enhances efficacy of cancer chemotherapy. Methods: Pts with untreated stage 4 NSCLC (total=56) received up to six courses of C, AUC=6, day 1 and G, 1.0 g/m2 days 1 & 8 in 21 day cycles and were randomized not to receive (Arm 1) or to receive (Arm 2) Dex 16 mg bid 4 days before and on days 1 & 8. Primary endpoint: incidence of grade 3/4 neutropenia and thrombocytopenia/cycle. Results: The Arms were balanced for age, sex, PS, histologic subtype, and no. of organ sites. Hematologic tox was reduced by Dex: Arm1 vs Arm 2 (dex): % cycles with grade 3/4 neutropenia, 40 vs 13 (p< 0.01), thrombocytopenia, 44 vs 23 (p < 0.03), and anemia, 7 vs 5 (p-ns). No statistically significant differences between Arms were observed in overall survival (OS), time to progression, quality of life measurements and non-hematologic tox. Partial responses in Arms 1 vs 2 were: 4/25 and vs 9/31 (p-ns). Stratification of pts by baseline CRP (> 1 ng/ml) and albumin (< 3.4 g/dl) into groups: # 1 (both normal), #2 (one abnormal), and #3 (both abnormal) was clearly predictive for OS (median in days): 724 (n=9) vs 288 (n=31) vs 187 (n=10) (p=0.01) and less so for incidence of grade 3/4 hematologic tox: 56 vs 61 vs 90% (p=0.19). Conclusions: These data suggest that Dex administered at this dose and schedule a) reduces grade 3/4 hematologic toxicity without adversely effecting QOL and efficacy and b) should be considered as a cost effective alternative ($6.40/cycle) to growth factor and platelet transfusion support. No significant financial relationships to disclose.
Survival by race among children with extracranial solid malignancies.
Authors: K. Johnson, R. Aplenc, R. Bagatell
Journal: Journal of Clinical Oncology (2010)

9559 Background: Previous studies of outcome by race in the pediatric oncology literature have focused in large part on children with leukemia and lymphoma. Data regarding outcomes by race for children diagnosed with extracranial sold tumors are limited, and little has been published regarding outcomes of patients from racial groups other than white or black. Methods: The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database was used to compare survival rates by race among patients diagnosed with common extracranial solid malignancies of childhood between 1985 and 2005. Survival trends for children diagnosed with eight common extracranial malignant solid tumors were evaluated using SEER 17 data. Five-year survival probabilities were calculated using the Kaplan-Meier method. Survival hazard ratios were calculated using a Cox proportional hazards model, and were compared for patients identified in SEER as white, black, and American Indian/Alaskan Native and Asians/Pacific Islander. Results: Five-year survival probabilities were higher for white children than for children belonging to either minority group (77% vs 72%, P < 0.05). The 5-year survival rate for male non-white children was lower than that of male white children (67% for black males and 68% for American Indian/Alaska Native + Asian/Pacific Islander males vs 77% for white males), while there were no differences in survival among females across racial groups. Compared to white children, black children had a higher risk of death overall (1.25, P < 0.05) and a higher risk of death from hepatoblastoma and non-rhabdomyosarcoma soft tissue sarcomas. American Indian/Alaskan Native and Asian/Pacific Islander children also had a higher risk of death overall (1.32, P < 0.05) and higher risks of death from germ cell tumors, hepatocellular carcinoma, neuroblastoma and Wilms tumor when compared to white children. Conclusions: Male children from minority groups have poorer survival from extracranial solid malignancies than do white male children. Future efforts should be directed at understanding the causes of these differences and on developing practical clinical interventions to eliminate them. No significant financial relationships to disclose.
Chemokine receptor 5 (CCR5) Δ32 base pair somatic gene deletions from PBM predict survival of patients with advanced stage (IV) melanoma
Authors: R. Essner, J. H. Lee, H. Itakura, Y. Huynh, R. Scheri, D. Morton
Journal: Journal of Clinical Oncology (2006)

10056 Background: Chemokines are a family of secreted chemotactic cytokines that function in leukocyte trafficking and activation. Chemokine receptor 5 (CCR5) is involved in CD4+ T-cell mediated immunity and dendritic cell (DC) activation. A 32 base pair (bp) deletion mutation on chromosome 3p21 result in a non-functional CCR5 with defective immunity. We hypothesized that CCR5Δ32 bp mutations would result in a diminished immune response to melanoma and maybe predictive of outcome of patients with advanced-stage disease. Methods: We identified 160 AJCC stage IV melanoma patients from our database whom had been made NED (no evidence of disease) by surgical resection. 105 (66%) had received active specific immunotherapy in phase I/II trials. Genomic DNA was extracted from peripheral blood mononuclear cells (PBM) and screened by PCR for the presence of CCR5Δ32 bp deletions. PCR products were sequenced to verify the result. Statistical analysis was performed by using Log-rank, Chi-square &amp; Student’s t-test. Results: Of 160 patients, 100 (63%) were men. Ages ranged from 19–82 (median 47 yrs.). 46 (29%) patients had M1a, 48 (30%) Mlb and 66 (41%) Mlc stage of metastases prior to surgical resection. Median follow-up was 47.5 mos. 135 (84%) patients had wild-type (Wt)CCR5 gene; 21 (13%) had heterozygous (HtM) and 4(3%) had homozygous mutations (HoM). 5-yr survival was significantly higher for patients with CCR5 Wt than those with HtM or HoM deletions (55.6%±6.1% vs. 21.4%±10.8%, p=0.031). None of the 21 patients with HtM survived 10yrs. Multivariate analyses demonstrated only CCR5 gene status (Wt vs. HtM/HoM) as predictive of survival (p=0.007). Age (p=0.23), gender (p=0.38), and M stage (M1a vs. M1b/c) (p=0.31) were not important in the statistical model. When immunotherapy responses (+ vs. -) were included in the model both responses and CCR5 mutation status were significant (p=0.0021, p=0.0063 respectively). Conclusions: Our results suggest CCR5Δ32bp somatic mutations from PBM are present in advanced-stage melanoma patients and are highly predictive of survival. Functional CCR5 may be used as a selection factor for surgery but more importantly essential for either active immunotherapy or the natural immune response to be effective for these patients. No significant financial relationships to disclose.
Phase I-II study of the combination vemurafenib plus peg-interferon in advanced melanoma patients harboring the V600BRAF mutation.
Authors: Paolo Antonio Ascierto, Keith Flaherty, Paola Queirolo, Ryan J. Sullivan, Vanna Chiarion-Sileni, Ruggero Ridolfi, Alessandro Testori, Ester Simeone, Antonio Maria Grimaldi, Francesco Sabbatino, Marcello Curvietto, Gennaro Ciliberto, Gerardo Botti, Nicola Mozzillo, Soldano Ferrone
Journal: Journal of Clinical Oncology (2014)

TPS9105 Background: Preliminary evidence in the literature suggests that interferon receptor subunit IFNAR1 is down-regulated in melanoma cells harboring a mutated active BRAF. This possibility is supported by our own finding that inhibition of the BRAF-MAPK signaling pathway by vemurafenib up-regulates IFNAR1 expression in BRAF mutated melanoma cells. Moreover, vemurafenib and IFNα-2b combination enhances HLA class I antigen expression which is associated with an increased recognition of melanoma cells by cognate T cells. A preclinical study has also showed the ability of vemurafenib and IFNα-2b combination to significantly prolong the survival of mice grafted with BRAF mutated melanoma cells. These findings have provided the rationale for designing a novel clinical trial. The study end-points include the evaluation of safety and efficacy of vemurafenib/PEG-interferon (PEG-IFN) combination. Methods: VEMUPLINT is an open-label, single-arm, phase I/II trial. Advanced melanoma patients with BRAF V600 mutation will be treated with vemurafenib and PEG-IFN combination (NCT01959633). Eligible patients include unresectable or metastatic melanoma, who have either not been treated or have received no more than 1 line of treatment. The primary end-point is the maximum tolerated dose (MTD) for the phase I study, while is the efficacy, assessed as durable response rate lasting > 32 weeks, for the phase II study. Primary end-points include also evaluation of IFNAR1 up-regulation. Secondary end-points are incidence of grade 3-4 toxicities, disease control rate, time to response, time to progression of brain metastases and overall survival. In the phase I study, groups of 3 patients for each cohort (9 patients) will be entered at each dose level (vemurafenib 960 mg b.i.d. + PEG-IFN 1/2/3 micrograms/Kg). The MTD will be considered the recommended dose for the phase II study. The phase II study will be conducted in approximately 10 investigational sites located in Italy; a total of 42 patients will be enrolled (including 3 patients from the phase I study). This phase I-II trial is currently recruiting patients for the phase I study at the Istituto Nazionale Tumori of Naples, Naples, Italy. Clinical trial information: NCT01959633.
Abstract 16995: Early Quantification of Left Ventricular Time-Volume Relation Detects Early Cardiotoxicity in Breast Cancer Patients Undergoing Adjuvant Chemotherapy: A Prospective Cardiac Magnetic Resonance Imaging Study
Authors: David Inyangetor, Ravi Marfatia, Richard S Feinn, Olurotimi Adekolu, Douglas Fellows, Susan Tannenbaum, Sheldon Litwin, Erick Avelar
Journal: Circulation (2013)
Abstract 18673: Fluoroscopy and High Voltage Testing - A Paradigm Shift in evaluation of Insulation Failure of Riata Lead
Authors: Umashankar Lakshmanadoss, Abhishek Kulkarni, David Lahoda, Angie Young, Mary Romanyshyn, Pramod Deshmukh
Journal: Circulation (2012)

Introduction: Current HRS guidelines for management of Riata lead recall are limited to close follow up. We have observed and reported high voltage testing (HVT) failure of Riata leads despite normal high resolution fluoroscopy (HRF) appearance and low voltage evaluation. We sought to assess the role of HRF and HVT to identify lead insulation defect. Methods: Patients with Riata leads were evaluated clinically and informed about the lead insulation issues. In addition to device interrogation, HRF examination and HVT testing were performed. Results: Out of 331 patients with Riata leads, 180 patients were seen in office. A total of 90 were screened with HRF and HVT. Separation of conductors was seen in 51% (46/90) and 9 % (8 patients) failed HVT (failed to induce/sense/shock VF). Out of 8 patients who failed HVT, 5 had normal HRF examinations. Retrospectively, additional 17 patients underwent lead extraction due to lead malfunction consistent with insulation failure. Lead extraction due to insulation defects were done in 36 /331 total pts and 19/90 screened patients (8 failed HVT, 8 patients for secondary prevention and externalized cables, 3 with externalized cables and on patient request). With 543 years of combined follow up(average 6 +1.3 years), prevalence of HRF detected insulation defect is 51% (46/90), 8.5%/year and malfunction consistent with insulation failure is 7.5% (25/331), 1.25%/year. Clinical examination, device interrogation, HRF and HVT has provided additional information and resulted in lead extractions in 19 patients (5 with normal and 14 with abnormal fluoroscopic appearance) despite of having normal low voltage parameters. Conclusions: Close follow up as suggested by HRS guidelines failed to identify high voltage integrity in 9% of patients. Additionally, 21% screened patients underwent lead extraction. These findings suggests the need of a larger prospective study incorporating the HRF and HVT to evaluate the integrity of Riata leads.
The Effect of Supplementary Choline on the Livers of Rats Fed &lt;italic&gt;p&lt;/italic&gt;-Dimethylaminoazobenzene&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/xref&gt;
Authors: Helen M. Dyer
Journal: JNCI Journal of the National Cancer Institute (1951)

Journal Article The Effect of Supplementary Choline on the Livers of Rats Fed p-Dimethylaminoazobenzene Get access Helen M. Dyer Helen M. Dyer National Cancer Institute, National Institutes of Health, U. S. Public Health Service, Bethesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 11, Issue 5, April 1951, Pages 1073–1080, https://doi.org/10.1093/jnci/11.5.1073 Published: 01 April 1951 Article history Received: 20 February 1950 Published: 01 April 1951