tbuckley/cabot-search huggingface dataset:
Abstract 85: Long-term Monotherapy with Bendavia (MTP-131), A Novel Mitochondria-Targeting Peptide, Restores H11 Kinase Protein Levels in Mitochondrial Fractions of Left Ventricular Myocardium of Dogs with Advanced Heart Failure
Authors: Ramesh C Gupta, Kristina Szekely, Mengjun Wang, Sharad Rastogi, Kefei Zhang, Paula Mohyi, Hani N Sabbah
Journal: Circulation Research (2014)

Background: The heat shock protein H11 kinase (H11K) is expressed in the heart of dogs, rodents and humans and rapidly increases in response to increased contractile workload. Deletion of H11K in pressure overload transgenic mice accelerates LV dysfunction and remodeling by deactivating STAT3, a stress-inducible transcription factor. Deactivation of STAT3 has been shown to adversely impact mitochondrial respiration and consequently oxidative phosphorylation. We previously showed that chronic therapy (3 months) with Bendavia (BEN, MTP-131), a novel mitochondria-targeting peptide, improves LV systolic function in dogs with heart failure (HF) and normalizes mitochondrial respiration and rate of ATP synthesis in LV myocardium of dogs with HF. This study tested the hypothesis that H11K is reduced in mitochondria of the failing heart and that long-term therapy with BEN normalizes levels of this key heat shock protein. Methods: LV tissue was obtained from 12 dogs with microembolization-induced HF (LV ejection fraction ~30%) randomized to 3 months therapy with subcutaneous injections of BEN (0.5 mg/kg once daily, n=6) or saline (Control, n=6). LV tissue from 6 normal dogs was used for comparison. Tissue samples were used to extract mitochondrial fractions (MF). Protein levels of H11K and Porin, a mitochondrial protein not altered in HF, were determined in MF by Western blotting and protein band were quantified in densitometric units (du). Results: Protein level of Porin in MF was similar among NL, Control and BEN-treated dogs (0.24±0.0 vs. 0.22±0.01 vs. 0.23±0.01 du, respectively). Level of H11K was 0.45±0.03 du in NL, decreased to 0.17±0.02 in Controls (p&lt;0.05vs. NL) and was normalized by BEN (0.37±0.05, p&lt;0.05 vs. Control). H11K normalized to Porin was 1.93±0.23 du in MF of NL dogs, decreased to 0.78±0.0.09 du in Controls (p&lt;0.05 vs. NL) and was restored to near normal levels after treatment with BEN (1.61±0.20 du, p&lt;0.05 vs. Control). Conclusions: H11K protein levels are reduced in MF from LV myocardium of dogs with HF and normalized after chronic therapy with BEN. Restoring H11K with BEN likely contributed to the observed improvement in mitochondrial respiration and rate of ATP synthesis previously reported after long-term therapy with BEN.
Ebola vaccine will be made available for emergency use
Authors: Anne Gulland
Journal: BMJ (2016)

Some 300 000 doses of a vaccine against Ebola virus disease will be available from May for use in emergency situations and clinical trials, under a deal signed by the drug company Merck and by Gavi, a vaccine provider to the poorest countries in the world.

Gavi has signed an advance purchase agreement with Merck that gives the drug company $5m (£3.5m; €4.6m) to develop the rVSV-ZEBOV-GP live attenuated Ebola Zaire vaccine.

The agreement is based on the understanding that 300 000 doses of the vaccine will be available for clinical trials or emergency use by May this year and that …
Calcium antagonists not best therapy for hypertension
Authors: David Spurgeon
Journal: BMJ (2000)

A meta-analysis of trials involving 27743 people has shown that calcium antagonists are inferior to other types of antihypertensive drugs as first line agents in reducing the risks of several major complications of hypertension, although they are equally effective in reducing blood pressure.

In an article in the Lancet, the researchers (from Wake Forest University, Winston Salem, North Carolina; the University of Washington, Seattle, Washington; and Albert Einstein College of Medicine, the Bronx, New York) concluded that “the longer-acting calcium antagonists cannot be recommended as first-line therapy for hypertension.”

Lead researcher Marco Pahor, professor of medicine at Wake Forest University's Baptist Medical Center, said: “We found that those treated with calcium channel blockers had a 26% higher risk of heart attack and a 25% higher risk of heart failure than those treated with other drugs.”
Phospho-ERK (pERK) and Ki67 expression as compared to thickness and mitotic rate (MR) as prognostic factors in patients with stage I/II melanomas
Authors: R. Edwards, D. Guerry, A. Piris, R. Elenitsas, J. Seykora, L. Schuchter, M. Mihm, X. Xu, P. Gimotty
Journal: Journal of Clinical Oncology (2008)

9020 Background: Tumor thickness and MR in the vertical growth phase (VGP) are key prognostic factors for melanoma patients. We hypothesized that the expression of two biomarkers associated with proliferation, Ki67, a measure of cell division, and pERK, a consequence of melanoma cells signaling through the MAP kinase pathway, would be associated with poor prognosis and more accurately predict those who would have a metastasis within ten years (MET). Methods: We evaluated Ki67 and pERK expression by immunohistochemistry in a nested cohort study of 50 patients with stage I/II VGP melanomas seen at Penn's Pigmented Lesion Clinic (1972–91). Ki67 expression was determined by the % of melanoma cells positive in VGP hot spots. Nuclear pERK expression by melanoma cells in the tumor's invasive edge (pERK/IE) was quantified using a modified H-score. Cut-points for both were established by maximizing the difference between survival distributions. Fisher's exact test (0.05, one-sided) had 75% power to detect an odds ratio (OR) of 4.3 with 19 and 42 patients with and without MET. Results: The odds of MET were 10.6-fold and 4.3-fold higher in patients having high Ki67 (p=0.013) and high pERK/IE (p<0.01) expression, respectively, compared to those with low expression. Thickness (OR=1.7, p=0.004) and MR (OR=1.3, p=0.002) were also each associated with MET. In the multivariate model the adjusted odds ratios for Ki67 and pERK/IE remained strong [4.0 (p=0.061) and 5.9 (p=0.030)], but thickness and MR were no longer significant. Conclusions: New biomarkers strongly associated with clinical outcome are needed. Both Ki67 and pERK/IE expression were strongly associated with prognosis, were notably more informative than thickness and MR in predicting MET, and are therefore candidates for validation in larger datasets. No significant financial relationships to disclose.
EPIG-19A METHYLATION CLASSIFICATION OF GLIOBLASTOMA THAT ACCURATELY PREDICTS GENE EXPRESSION SUBTYPE
Authors: Jie Yang, Qianghu Wang, Raveshanker Ezhilarasan, Mona Jaffari, Adriana Olar, Roeland Verhaak, Erik Sulman
Journal: Neuro-Oncology (2015)

Glioblastoma (GBM) is the most common primary malignant brain tumor and is invariably lethal. Past studies have shown that classification based on genomic data can potentially help in understanding this devastating tumor better. In 2013, TCGA proposed a six-subgroup classification (M1-M4, G-CIMP, and M6) based on methylation profiles. However, with the exception of G-CIMP, the subgroups did not show significant molecular differences. We aimed to develop a more informative and robust methylation classification system to better integrate molecular profiles of GBM. By using the publicly available Illumina Infinium 450K Bead Array methylation data on 414 primary GBM samples from the TCGA, a new classification was generated. The classification was validated with Glioma stem-like cells (GSCs) (n = 42). The beta-mixture quantile normalization (BMIQ) method was applied and the most variant probes were selected based on the median absolute deviation (MAD) value. Samples and probes were clustered with the consensus non-negative matrix factorization (CNMF) method and 78 representative probes were selected for each of the four clusters obtained. CNMF clustering was reapplied to all samples with these 312 probes and the final classification model was developed (named as cluster S1 to S4). Each methylation cluster exhibited unique copy number variants and somatic mutation patterns, better reflecting the biology of GBM compared to the reported TCGA methylation classification. Additionally, each methylation cluster showed enrichment of specific gene expression subtypes: S1-mesenchymal (82.1%), S2-classical (64.4%), S3-CIMP positive proneural (90.6%), and S4-CIMP negative proneural (74.3%). The GSC validation cohort reflected identical gene expression subtype, copy number variation, and somatic mutation enrichment. In conclusion, we have developed a biologically relevant methylation classification based on Illumina 450K Bead Arrays which successfully correlates to expression subtype. This classification can be used as a diagnostic tool to assign appropriate therapies based on the genomic targets identified in the methylated classes.
Impact of the outpatient clerkship on medical students
Authors: P F Eagle, L R Marcos
Journal: American Journal of Psychiatry (1980)

Using an anonymous questionnaire, the authors assessed the professional relevance of outpatient and inpatient curricula and the didactic value of different parts of the clerkship for 80 junior medical students randomly assigned to a pilot clerkship. Significantly more medical students preferred outpatient to inpatient psychiatry; they supported the view that working with outpatients is more useful, rewarding, and educational for the nonpsychiatrist physician. The implications of this study include the need to increase the outpatient psychiatric experience in medical school, the importance of surveying the impact of learning settings on students, and the reasonableness of adapting the curriculum to the didactic needs of students.
A roadmap of constitutive NF-κB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses
Authors: Kivia A. P. de Oliveira, Eva Kaergel, Matthias Heinig, Jean-Fred Fontaine, Giannino Patone, Enrique M. Muro, Stephan Mathas, Michael Hummel, Miguel A. Andrade-Navarro, Norbert Hübner, Claus Scheidereit
Journal: Genome Medicine (2016)

Background: NF-κB is widely involved in lymphoid malignancies; however, the functional roles and specific transcriptomes of NF-κB dimers with distinct subunit compositions have been unclear.Methods: Using combined ChIP-sequencing and microarray analyses, we determined the cistromes and target gene signatures of canonical and non-canonical NF-κB species in Hodgkin lymphoma (HL) cells.Results: We found that the various NF-κB subunits are recruited to regions with redundant κB motifs in a large number of genes.Yet canonical and non-canonical NF-κB dimers up-and downregulate gene sets that are both distinct and overlapping, and are associated with diverse biological functions.p50 and p52 are formed through NIK-dependent p105 and p100 precursor processing in HL cells and are the predominant DNA binding subunits.Logistic regression analyses of combinations of the p50, p52, RelA, and RelB subunits in binding regions that have been assigned to genes they regulate reveal a cross-contribution of p52 and p50 to canonical and non-canonical transcriptomes.These analyses also indicate that the subunit occupancy pattern of NF-κB binding regions and their distance from the genes they regulate are determinants of gene activation versus repression.The pathway-specific signatures of activated and repressed genes distinguish HL from other NF-κB-associated lymphoid malignancies and inversely correlate with gene expression patterns in normal germinal center B cells, which are presumed to be the precursors of HL cells.Conclusions: We provide insights that are relevant for lymphomas with constitutive NF-κB activation and generally for the decoding of the mechanisms of differential gene regulation through canonical and non-canonical NF-κB signaling.
Panobinostat, An Oral Pan-Histone Deacetylase (HDAC) Inhibitor Activates a Microrna Signature That Targets Rad51 To Attenuate Homologous DNA Repair and Sensitize AML Cells To Sapacitabine
Authors: Deepa Sampath, Alma Zecevic, Brett Ewald, Melanie Hayes, Chaomei Liu, Guido Marcucci, William Plunkett
Journal: Blood (2013)
Phase I Trial of Intraperitoneal Nab-Paclitaxel in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity
Authors: M.C. Cristea, S. Rivkin, D. Lim, V. Chung, J. Chao, M. Wakabayashi, B. Paz, E. Han, P. Lin, L. Leong, A. Hakim, P. Frankel, T. Synold, M. Carroll, H. Openshaw, N. Prakash, T. Dellinger, M. Park, R. Morgan
Journal: Annals of Oncology (2014)
Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days
Authors: Q. S. Chu, K. D. Holen, E. K. Rowinsky, G. Wilding, J. L. Volkman, J. B. Orr, D. D. Williams, J. P. Hodge, J. Sabry
Journal: Journal of Clinical Oncology (2004)

2078 Background: The mitotic kinesin KSP plays an exclusive and essential role in assembly and function of the mitotic spindle. KSP represents a novel target for development of therapeutics against cancer. SB-715992 is a unique and selective inhibitor of KSP, that is preferentially overexpressed in malignant cells, functions exclusively in mitosis, and is not expressed in terminally differentiated neurons. In pre-clinical studies in a broad range of human tumor xenografts, doses of SB-715992 below the MTD produced tumor regression and cures. Methods: A phase I study was conducted to determine the MTD, safety, and PK profile of SB-715992 Q 21 d IV.Results: 42 patients (pts) (M/F 31/11) with solid tumors were treated at doses of 1 to 21 mg/m2. Median age 61 years (range 37–85). Common tumor types included CRC (15), RCC (5) sarcoma (4), and lung (4). 2 pts developed DLT at 21 mg/m2 consisting of Grade (Gr) 4 neutropenia ≥ 5 days (1 pt) and Gr 4 neutropenic fever (1 pt). The 18 mg/m2dose level was expanded as a recommended phase II dose; 12 pts (18 cycles of safety data) have been treated. 2 DLTs have been observed at this dose level consisting of Gr 4 neutropenia ≥ 5 d; non-dose limiting Gr 3 or 4 neutropenia and Gr 4 leukopenia occurred in 7 (58%) and 1 (8%) pts. Neutropenic nadir occurred on day 8 and lasted 2–4 d. Common ≥ Gr 2 drug related toxicities at ≥ 6 mg/m2 included fatigue, leukopenia, and anemia. SD was observed for 5–11 cycles in 4 pts with CRC, HCC, SCCHN, & RCC. Increases in AUC0-∞and Cmax were dose-related. For the 18 mg/m2 dose level in Cycle 1, median PK values (n=6) were Cmax = 473 ng/mL; AUC0-∞= 5074 ng.h/mL; t1/2 = 33 hrs; CL = 6656 mL/hr; and Vss = 236 L. Monopolar mitotic spindles were observed in a tumor biopsy from a pt w/ SCCHN at 16 mg/m2.Conclusion: Based on the toxicities noted, 18 mg/m2 Q 21 d IV, which has been demonstrated to induce relevant biological effects in vivo, is recommended for phase II investigations. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cytokinetics, Inc.
Abstract 3546: Arming a tumor targeted oncolytic herpes simplex sirus type 1 with matrix metalloproteinase 9 for enhanced vector distribution and killing activity
Authors: Aofei Li, Marco Marzulli, Mingdi Zhang, William Goins, Balveen Kaur, Chelsea Bolyard, Nduka Amankulor, Daniela Leronni, Paola Sette, Justus Cohen, Joseph Glorioso, Paola Grandi
Journal: Cancer Research (2015)

Abstract Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment of GBM, but efficacy has been limited. Impediments to oHSV therapy include poor virus spread due in part to the tumor extracellular matrix, and insufficient replication in tumor cells as a result of attenuating mutations. Thus, the central goal of this project is to improve oncolytic vector delivery, replication and spread while maintaining safety and tumor specificity. We have already developed a new class of two stage tumor targeted oHSV combining (i) selective infection through tumor-specific receptors and (ii) selective replication based on differential expression of microRNAs (miRs) in tumor and normal cells. We further modify our vector by arming with the matrix metalloproteinase 9 (MMP9) as a means to reduce vector trapping in the tumor extracellular matrix. Here we show that MMP9 expression (i) enhances Oncolytic vector spreading in GBM neruospheres in vitro and (ii) improves tumor killing in a xenogeneic model of primary human GBM with significant long-term survival (≥50%) comparable to the control. Citation Format: Aofei Li, Marco Marzulli, Mingdi Zhang, William Goins, Balveen Kaur, Chelsea Bolyard, Nduka Amankulor, Daniela Leronni, Paola Sette, Justus Cohen, Joseph Glorioso, Paola Grandi. Arming a tumor targeted oncolytic herpes simplex sirus type 1 with matrix metalloproteinase 9 for enhanced vector distribution and killing activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3546. doi:10.1158/1538-7445.AM2015-3546
Racial differences in receipt of guideline-recommended treatment in men with low-, intermediate-, and high-risk prostate cancer (CaP): A population-based study.
Authors: R. C. Chen, J. Bainbridge, W. R. Carpenter, Z. A. Wang, M. E. Nielsen, J. Darter, P. A. Godley
Journal: Journal of Clinical Oncology (2010)

9002 Background: Compared to Caucasian men, African American (AA) men are more likely to develop more advanced disease and die from CaP. The recent incorporation of Gleason score and prostate-specific antigen (PSA) into Surveillance, Epidemiologic and End Results (SEER) allows examination of guideline-recommended treatment selection as a modifiable factor of the CaP mortality outcome disparity. Methods: 12,197 Caucasian and 2,362 AA men diagnosed in 2004-5 with localized CaP, age 65 or older, were drawn from SEER registries with at least 5% of AA population. Gleason, PSA and clinical stage were used for risk-categorization. Medicare claims data were used to determine initial treatment received. The National Comprehensive Cancer Network (NCCN) guidelines were used to determine if patients received recommended treatment. Fisher's exact test was used to determine statistical significance. Logistic regression was used to examine the odds of receiving NCCN treatment while accounting for risk group, age, comorbidity, marital status, and SEER region. Results: In stratified analysis, 77-81% of Caucasian and AA men with low- and intermediate-risk CaP received NCCN treatments. Among high-risk patients, AA vs. Caucasian men were less likely to receive NCCN treatments (39% vs. 46%, p<.01), including 29% who received no treatment within 8 months of diagnosis (vs. 20% Caucasian) and 29% hormonal treatment only (vs. 26% Caucasian). Racial differences in receipt of guideline-recommended treatment persisted in multivariable modeling for the entire cohort (Table). Conclusions: AA men are less likely to receive guideline-recommended treatment, especially those with high-risk CaP. The differences in the proportion of patients receiving recommended therapy may contribute to our understanding of racial disparities in CaP treatment outcomes. Covariate OR 95% CI P value AA (vs. Caucasian) 0.80 0.72, 0.88 <0.01 Risk group (vs. low risk) Intermediate 0.94 0.83, 1.06 0.29 High 0.23 0.20, 0.25 <0.01 Age (vs. 65-69) 70-74 0.89 0.80, 0.99 0.03 <75 0.41 0.38, 0.46 <0.01 NCI combined index score (comorbidity) 0.74 0.68, 0.80 <0.01 Married (vs. not) 1.30 1.19, 1.42 <0.01 Controls for SEER region. No significant financial relationships to disclose.
Predictive Molecular Markers: Has the Time Come for Routine Use in Lung Cancer?
Authors: Angela M. Davies, Philip C. Mack, Primo N. Lara, Derick H. Lau, Kathleen Danenberg, Paul H. Gumerlock, David R. Gandara
Journal: Journal of the National Comprehensive Cancer Network (2004)

Although some evidence exists to support the use of clinical factors such as performance status and weight loss to predict response and toxicity to therapy in non-small cell lung cancer (NSCLC) patients, researchers have shown little prospective data on the use of molecular markers to facilitate selection of specific chemotherapy or new molecularly targeted agents in this patient population. Breast cancer exemplifies the growing role that molecular markers are playing, not only as prognostic factors, but also in predicting response to targeted treatments such as hormonal therapy, and more recently, trastuzumab (Herceptin). Although several studies have examinedmolecular markers in lung cancer and have shown promising potential value, these studies were retrospective and require prospective validation. To identify molecular markers that reliably predict response and to be able to individualize cytotoxic and targeted therapy for NSCLC patients are the ultimate goals of future trials. This article focuses on a selected number of promising markers under study in lung cancer, including those thought to play roles in response to DNA damaging chemotherapy (excision repair cross-complementing [ERCC1], xeroderma pigmentosum group D [XPD]), taxane resistance (-tubulin III), antimetabolite therapy (RRM1), irinotecan metabolism (UGT1A1) and epidermal growth factor receptor (EGFR) pathway inhibition. To date, none of these markers can be recommended for routine use in clinical practice.
Naturally Occurring Cell-Mediated Cytotoxicity Against Simian Virus 40-Transformed 3T3 Murine Tumor Cells<xref ref-type="fn" rid="fn2">2</xref><xref ref-type="fn" rid="fn3">3</xref>
Authors: M C Kanar, A Winkelstein, D Platt
Journal: JNCI Journal of the National Cancer Institute (1983)

The tumorigenicity and host protective mechanisms induced by simian virus 40 (SV40)-transformed 3T3 cells (SV403T3) were evaluated in syngeneic BALB/c mice. Tumors were regularly produced by sc inoculation of SV403T3 cells; the incidence, latent period, and survival were proportional to the size of the initial inoculum. With the use of an in vitro 18-hour 51Cr cytotoxicity assay, spleen cells from normal mice showed a dose-related killing activity against the SV403T3 cells. At an effector cell-to-target cell ratio of 200:1, the average lysis was 56 +/- 6%. This reaction appeared specific for the virally transformed targets; the mean lysis of parent 3T3 cells was 23 +/- 5%. Effectors were resistant to anti-theta serum and not removed by adherence to plastic or nylon wool. Tissue distribution studies indicated that these effectors were present in high concentrations in spleen, bone marrow, lymph nodes, and peritoneal cavity. Low levels of activity were associated with cells from the thymus. In the present studies specific T-cell cytotoxicity against the SV403T3 cells could not be demonstrated. Animals challenged with nonviable SV403T3 cells prior to tumor cell inoculation did not show increased in vivo resistance. In parallel, the in vitro cytotoxicity of animals inoculated with SV403T3 tumor cells showed no heightened cell killing compared to the cytotoxicity of normal controls.
Abstract 17550: Plasmalemma Vesicle-Associated Protein Promotes Angiogenesis by Stimulation of the Endothelial Production of Pro-Angiogenic Sphingosine 1-Phosphate
Authors: Dennie Tempel, Lisanne van Dessel, Petra Burgisser, Caroline Cheng, Gerard Pasterkamp, Stefan Schulte-Merker, Henricus Duckers
Journal: Circulation (2013)

Although the molecular mechanisms that govern the formation of a vascular network have been studied intensively, many molecular players still remain unknown or not well understood. To identify pote...
Relevance of &bgr;ß-Gal-ß-GalNAc-containing O-glycans and the enzymes involved in their synthesis for vascular and lymphatic invasion and survival in breast cancer patients
Authors: K. Milde-Langosch, L. Oliveira-Ferrer, D. Schütze, H. Wikman, I. Witzel, C. Schröder, K. Pantel, U. Schumacher, V. Müller
Journal: Annals of Oncology (2015)