tbuckley/cabot-search huggingface dataset:
Abstract 129: Integrated genomic analysis of survival outliers in glioblastoma
Authors: Sen Peng, Harshil Dhurv, Brock Armstrong, Jeffrey Kiefer, Bodour Salhia, Julianna Ross, Christophe Legendre, Selene Virk, Andrew E. Sloan, Quinn T. Ostrom, Jill Barnholtz-Sloan, Nhan L. Tran, Michael E. Berens
Journal: Cancer Research (2016)

Abstract Despite the general poor prognosis for patients with GBM, a proportion survives well beyond the median survival of 12-14 months following diagnosis. To elucidate molecular features associated with disproportionately protracted survival, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide) wherein “GBM outliers” were identified: patients who responded (long-term survivor, LTS) versus those who failed rapidly (short-term survivor, STS). The datasets enabled interrogation for signatures indicative of tumor vulnerability. Whole genomic, transcriptomic and epigenetic analyses of 18 patients, including 8 LTS with an average 30 months overall survival (OS) and 10 STS with an average of 7 months OS were performed to capture single nucleotide variants (SNVs), indels, translocations, intra-chromosomal rearrangements, copy number variants, along with DNA methylation and mRNA expression. LTS and STS cases showed equal proportion of 7p11.2 (EGFR) amplification and 9p21.3 (CDKN2A) deletion. However, LTS GBM showed frequent chromosomal gains in 4q12 (PDGFRA and KIT) and 12q14.1 (CDK4) and deletion in 19q13.33 (BAX, BCAT2 and CD33), whereas, STS GBM showed frequent deletion in 9p11.2 (FOXD4L2 and AQP7P3) and 22q11.21 (HIC2). In addition, LTS GBM showed a 2-fold increased copy number alteration (specifically deletion) as compared to STS GBM. By gene expression analysis, supervised clustering using the CIN70 signature (prognostic) showed an increased expression in STS GBM. Overall, whole genome methylation analyses showed that STS GBM tumors harbor more hypomethylation in probes situated in -200 bp of transcription start site (TSS) and both exon 1 and 5’UTR region. A methylation signature consist of 89 probes distantly separate LTS from STS GBM tumors. We posit that genomic instability (broadly inclusive) is associated with vulnerability of GBM to standard therapy; conversely, genomic instability coupled with genetic and epigenetic signatures may identify patients where up-front entry into alternative, targeted regimens would be a preferred, more-efficacious management. Supported by a grant from the Ben &amp; Catherine Ivy Foundation. Citation Format: Sen Peng, Harshil Dhurv, Brock Armstrong, Jeffrey Kiefer, Bodour Salhia, Julianna Ross, Christophe Legendre, Selene Virk, Andrew E. Sloan, Quinn T. Ostrom, Jill Barnholtz-Sloan, Nhan L. Tran, Michael E. Berens. Integrated genomic analysis of survival outliers in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 129.
Phase 1 pharmacokinetic (PK) and pharmacodynamic(PD) evaluation of SF1126 a vascular targeted pan phosphoinositide 3- kinase (PI3K) inhibitor in patients with solid tumors
Authors: U. S. Schwertschlag, E. G. Chiorean, S. P. Anthony, C. J. Sweeney, M. J. Borad, D. D. Von Hoff, J. R. Garlich, C. F. Shelton, R. K. Ramanathan
Journal: Journal of Clinical Oncology (2008)

14532 Background: SF1126 is a conjugate of the well known pan PI3K inhibitor LY294002 with an RGD containing peptide designed for increased solubility and binding to specific integrins within the tumor compartment. This prodrug approach has been demonstrated to enhance delivery of the active inhibitor to the tumor resulting in increased antitumor efficacy coupled with improved tolerability in a number of preclinical studies including PC-3, DU-145, U87MG, U251MG, LN229, 786-O, MDA-MB-468 xenograft/orthotopic cancer models (Cancer Research, 2008;68(1)pp206–15). Methods: Patients are being dosed twice/ week by IV infusion over 1.5 hours in treatment cycles of 4 weeks. This is a dose escalation study with patients being entered onto a 3+3 modified Fibonacci schema. Activity of SF1126 is assessed by standard RECIST criteria, PD effects by 18F-deoxygluose PET scans 4 - 8 hours after dosing and at the end of cycle 1 and by enumeration of tumor cells. Results: To date 10 patients have been treated with SF1126 twice/ week for up to six months, the average treatment duration was 2 months (2 cycles). The dose escalation has progressed from 90 mg/m2 to 140 mg/m2 and to 180 mg/m2. One dose limiting toxicity (DLT) was seen at the 180 mg/m2 dose and consisted of a hypersensitivity reaction manifested by hypotension and also diarrhea. In general the drug was well tolerated, 1 patient discontinued study because of an SAE, the remainder of the patients discontinued study for disease progression. The analysis of blood samples for parent drug (SF1126) and the hydrolysis product SF1101 (LY294002) showed a clearance and T1/2 values of CL: 178 ± 68 L/hr and T1/2 of 1.21 ± 0.58 hr respectively. Parent drug was measurable in some subjects at 5 and 15 min post-infusion, but not at any of the later sampling times. Intrapatient variability was low and subgroup of slow metabolizers is likely. Conclusions: SF1126 is well tolerated and converted in plasma rapidly to SF1101, which has a T1/2 of 1.2 ± 0.58 hrs. Dose escalation continues at 180 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Semafore Pharmaceuticals
Abstract 5071: Expression and cellular distribution of Profilin1/VASPp157and cofilin1/VASPp239is altered by docosahexaenoic acid and suppresses cancer cell migration and survival
Authors: Mehboob Ali, Kathryn M. Heyob, Lynette K. Rogers
Journal: Cancer Research (2016)

Abstract The major risk factor for cancer associated death is uncontrolled metastasis and longer cancer cell survival. Mechanisms associated with actin binding protein-mediated actin dynamics and subcellular distributions are not well defined. Secondary messengers (cAMP and cGMP)differentially phosphorylate actin binding proteins like VASP and are associated with actin remodeling in cancer cells. We tested the hypothesis that differential phosphorylation of VASP precipitates association with two additional actin binding proteins, profilin1 and cofilin1. Furthermore, we speculate that the associations of VASP with profilin1 or cofilin1 are causing changes in subcellular location of the protein complexes. Briefly, non-invasive lung epithelial (MLE12) and cancer (A549) cells were treated with 8-Br-cAMP and/or DHA for 6h and 24h. Actin binding proteins (profilin1, cofilin1, VASP, VASPp157and VASPp239) expressions were analyzed by western blot in cell lysate. Wound assay and transwell apparatus were used to study cell migration. Confocal analysis was performed to analyze F-actin content and actin binding proteins at the wound leading edges and in human lung cancer biopsy samples. Flow cytometry, using ki-67, and cleaved-caspase-3 antibodies were performed to study proliferation and cell viability. Our data indicate an association between profilin1/VASPp157 and cofilin1/VASPp239 and changes in the relative cytoplasmic/nuclear distribution of these protein complexes that coincide with the invasive potential of the cell line or tissue. Additional studies showed that docosahexaenoic acid, inhibited cancer cell migration and viability and altered the expression and cellular distribution of profilin1/VASPp157 and cofilin1/VASPp239. In summary, profilin1/VASPp157 and cofilin1/VASPp239 protein complex expression and subcellular distribution could serve as novel, new areas of research, as biomarkers of disease progression, and/or as innovative therapeutic targets against metastasis. Citation Format: Mehboob Ali, Kathryn M. Heyob, Lynette K. Rogers. Expression and cellular distribution of Profilin1/VASPp157 and cofilin1/VASPp239 is altered by docosahexaenoic acid and suppresses cancer cell migration and survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5071.
PWE-033 Abundance of sulphate reducing bacteria in inflammatory bowel disease
Authors: W Jia, L Griffiths, R Whitehead, S J Basser, C Dawson, C Turner, C Bessant, D Fowler, C Walton, D Ramsden, R Waring, J Cole, J O Hunter
Journal: Gut (2010)

<h3>Introduction</h3> As one of the possible causes of inflammatory bowel disease (IBD), the microbiota in the human gut has been widely studied. Sulphate-reducing bacteria (SRB) have long been considered as candidate pathogens because their metabolic product, sulphide, through its toxic properties, damages the colonic epithelium. However, no specific SRB has been identified as a pathogen to IBD, and even their abundance in the human gut remains controversial. This project compares the amount of faecal SRB in healthy subjects with that in patients either with Crohn9s disease (CD) or ulcerative colitis (UC), and traces the change, if any, after treatment in each patient. <h3>Methods</h3> Faecal samples were collected from 18 healthy subjects, 18 CD patients and 14 UC patients. CD patients were treated with elemental diet and UC patients received conventional treatment. A suspension of the faecal matter from each patient both before and after treatment was inoculated into a sulphate-rich growth medium, Postgate B. The abundance of SRB was gauged according to the amount of black precipitate (ferrous sulphide) formed by SRB. <h3>Results</h3> Contrary to expectation 88% of healthy subjects carry SRB that produce high levels of sulphide in vitro, despite its cytotoxicity in vivo. In contrast, this carriage rate is low (45%) in CD patients at their initial presentation. After taking elemental diet, the carriage rate of active SRB did not change despite a significant fall in the total amount of gut bacteria. In UC patients, who are often characterised with mucus depletion, the carriage rate of active SRB is significantly lower (31%, p&lt;0.05) when compared to healthy control. This finding is consistent with a previous proposal that sulphate in mucins rather than that in undigested food is the energy source for SRB. After conventional treatment, the carriage rate increased from 31% to 69%. <h3>Conclusion</h3> In healthy subjects, SRB that produce high levels of sulphide in vitro are prevalent in the human gut but do not cause adverse effects. An impaired mucous sulphation might be associated with most of UC patients who carry low levels of active SRB.
Doctor should be able to help dying man commit suicide, rules South African judge
Authors: P. Sidley
Journal: BMJ (2015)

A South African High Court judge has ruled in favour of a dying man’s wish to be assisted in his suicide by a doctor. Robin Stransham-Ford, who was 65, had prostate cancer and had only a few weeks to live. He died, however, of “natural causes,” said a statement released by his family before he learnt of his court victory.

Stransham-Ford was himself a lawyer (a barrister) and had made an urgent application to court on Wednesday, helped by the lobby group Dignity SA, to ask the court to enable him to die with the help of a doctor. The application was opposed by the Department …
Abstract 1053: Redirecting abiraterone metabolism to biochemically fine tune prostate cancer therapy
Authors: zhenfei li, Mohammad Alyamani, Nima Sharifi
Journal: Cancer Research (2016)

Abstract Prostate cancer is the most diagnosed cancer in men and Abiraterone is used for castration resistant prostate cancer therapy by suppressing androgen production. In patients, abiraterone is converted to D4A, a novel metabolite with more potent anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is further metabolized by the related steroidogenic enzymes to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial with patients taking abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted by dutasteride, while D4A concentrations rise, effectively blocking production of a tumor promoting metabolite and permitting D4A accumulation. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine tuning abiraterone metabolism to optimize therapy. Citation Format: zhenfei li, Mohammad Alyamani, Nima Sharifi. Redirecting abiraterone metabolism to biochemically fine tune prostate cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1053.
Tacrolimus (FK) Compared to Cyclosporine a (CyA) after Haploidentical T Cell Replete Stem Cell Transplantation (Haplo-SCT) with Post-Infusion Cyclophosphamide: A Retrospective Analysis
Authors: Luca Castagna, Stefania Bramanti, Sabine Furst, Barbara Sarina, Roberto Crocchiolo, Laura Giordano, Jean El Cheikh, Angela Granata, Lucio Morabito, Elisa Mauro, Catherine Faucher, Bilal Mothy, Samia Harbi, Christian Chabannon, Carmelo Carlo-Stella, Armando Santoro, Didier Blaise
Journal: Blood (2014)
PTPS-17LEPTOMENINGEAL METASTASIS IN MYC-DRIVEN MEDULLOBLASTOMA
Authors: Kun-Wei Liu, Vijay Ramaswamy, Michael Taylor, Robert Wechsler-Reya
Journal: Neuro-Oncology (2015)

Medulloblastoma (MB) is the most common malignant brain tumor in children. Even with an intensive regimen of surgery, radiation and chemotherapy, 25-30% of MB patients still die from their disease. Recent genomic analyses of MB have shed light on the molecular basis of the disease and have begun to point to novel approaches to therapy. However, the vast majority of these studies have focused on primary tumors, and relatively few have examined the biology of leptomeningeal metastasis (LM), the spread of tumor cells through the meninges to the brain and spinal cord. LM, most commonly seen in patients with MYC-driven (Group 3) MB, is not amenable to surgical resection and is associated with extremely poor patient outcomes. To understand the mechanisms driving metastasis, we used a mouse model of MYC-driven MB in which tumor cells exhibit LM. Importantly, we found that when primary and metastatic cells from this model are injected into the cerebrospinal fluid, primary cells tend to give rise to primary tumors whereas metastatic cells are more likely to regenerate metastatic lesions. To identify pathways that mediate this difference in metastatic potential, we compared gene expression in primary vs. metastatic tumor cells from our animal model, as well as from MB patients. Our studies revealed activation of signaling pathways involved in cell motility and adhesion to the extracellular matrix, and identified genes that are commonly activated in the metastatic compartment in both mouse and human MB. Ongoing studies are focused on validating differential expression of these genes and determining their function using in vitro and in vivo assays. These studies will provide critical insight into the mechanisms of metastasis in MB and yield novel approaches for treating metastatic disease.
Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial
Authors: M.V. Dieci, A. Prat, E. Tagliafico, L. Paré, G. Ficarra, G. Bisagni, F. Piacentini, D.G. Generali, P. Conte, V. Guarneri
Journal: Annals of Oncology (2016)
Potent Induction of Human γ Globin Gene Expression by Largazole, a New Histone Deacetylase Inhibitor.
Authors: Hua Cao, Rui Gao Fei, Albert A. Bowers, Thomas J. Greshock, Tenaya Newkirt, Kenneth A. Miller, James E. Bradner, Nathan West, Robert M. Williams, Thalia Papayannopoulou, George Stamatoyannopoulos
Journal: Blood (2009)
Abstract 4524: A rational approach for the discovery of inhibitors of NSD2 for the treatment of multiple myeloma
Authors: Claudia Fromond, Xavier Espanel, Severine Estevez, Vanessa Adarbes, Stephanie Bocart, Bruno Loillier, Anne Soude, Nathalie Urban, Frederic Bell, Philippe Masson, Benaïssa Boubia, Pierre Broqua, Christian Montalbetti
Journal: Cancer Research (2016)

Abstract Multiple myeloma (MM) is a plasma cell malignancy which accounts for approximately 10% of hematologic malignancies. Despite the introduction of new therapeutic agents, MM remains incurable and nearly all patients ultimately relapse. About 20% of MM are due to a chromosomal translocation t(4;14) leading to overexpression of the NSD2 histone methyltransferase. NSD2 catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Several studies have shown that in MM harboring the translocation t(4;14), oncogenic programming is dependent on the methyltransferase activity of NSD2. Thus, NSD2 inhibitors are potential therapeutics for this devastating cancer Using the AlphaLisa™ technology, we screened 240,000 compounds coming from our proprietary library. The assay was based on the detection of H3K36me2 on nucleosome by a specific antibody. False positives hits were removed by a technological counterscreen, and compounds with redox or metal contamination activity were excluded. For confirmation purposes, an orthogonal counter-screen based on 3H SAM incorporation was performed. The IC50 obtained for one of the best compounds across the AlphaLisa and 3H SAM incorporation are very similar, showing values of 0.15 μM and 0.29 μM respectively for compound 1. Binding affinities measured by MST and SPR for compound 1 were consistent with the IC50 observed in the biochemical assays KD = 0.19 μM for MST and 1.7 μM by SPR. This compound was also shown to be a good binder by NMR (STD), and further experiments are planned to elucidate the selectivity and MOA of this series. To our knowledge, no NSD2 inhibitor have been identified to date despite several screening efforts performed by other groups. We believe that our hits are promising starting points to generate potent and selective NSD2 inhibitors. Citation Format: Claudia Fromond, Xavier Espanel, Severine Estevez, Vanessa Adarbes, Stephanie Bocart, Bruno Loillier, Anne Soude, Nathalie Urban, Frederic Bell, Philippe Masson, Benaïssa Boubia, Pierre Broqua, Christian Montalbetti. A rational approach for the discovery of inhibitors of NSD2 for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4524.
High prevalence of anti-hepatitis E virus antibodies among blood donors in central Italy, February to March 2014
Authors: Claudia Lucarelli, Enea Spada, Gloria Taliani, Paola Chionne, Elisabetta Madonna, Cinzia Marcantonio, Patrizio Pezzotti, Roberto Bruni, Giuseppina La Rosa, Giulio Pisani, Luigi Dell'Orso, Katia Ragone, Carla Tomei, Anna Rita Ciccaglione
Journal: Eurosurveillance (2016)

Prevalence of anti-hepatitis E virus (HEV) antibodies is highly variable in developed countries, which seems partly due to differences in assay sensitivity. Using validated sensitive assays, we tested 313 blood donors attending a hospital transfusion unit in central Italy in January and February 2014 for anti-HEV IgG and IgM and HEV RNA. Data on HEV exposure were collected from all donors. Overall anti-HEV IgG prevalence was 49% (153/313). Eating raw dried pig-liver sausage was the only independent predictor of HEV infection (adjusted prevalence rate ratio = 2.14; 95% confidence interval: 1.23-3.74). Three donors were positive for either anti-HEV IgM (n = 2; 0.6%) or HEV RNA (n = 2; 0.6%); they were completely asymptomatic, without alanine aminotransferase (ALT) abnormalities. Of the two HEV RNA-positive donors (both harbouring genotype 3), one was anti-HEV IgG- and IgM-positive, the other was anti-HEV IgG- and IgM-negative. The third donor was positive for anti-HEV IgG and IgM but HEV RNA-negative. HEV infection is therefore hyperendemic among blood donors (80% men 18-64 years-old) from central Italy and associated with local dietary habits. Nearly 1% of donors have acute or recent infection, implying potential transmission to blood recipients. Neither ALT nor anti-HEV IgM testing seems useful to prevent transfusion-transmitted HEV infection.
G-CSF-Primed Allogeneic-BMT Following Reduced Intensity Conditioning (RIC) Regimen for Patients with AML. Rapid Engraftment, Low Incidence of Chronic Gvhd (cGVHD) and Good Outcome for Patients In 1 st Complete Remission (CR), but Not for More Advanced Cases
Authors: Mauricio Ostronoff, ANA Patricia Souto Maior, Fabiana Ostronoff, Rodrigo Florencio, Monique Martins, Luis Fabio Botelho, Alexandre Sucupira, Mariana Coutinho, Rodolfo Calixto
Journal: Blood (2010)
Reduced Polyethylene Glycol-Conjugated B-Domain–Deleted Factor VIII (PEG-BDD-FVIII) Clearance: Selective Peg Steric Modulation without Affecting Potency
Authors: Eric Blasko, Lilley Leong, Derek S Sim, Liang Tang, Elena Ho, Jim Wu, Katalin Zsofia Kauser, Babu Subramanyam
Journal: Blood (2014)