tbuckley/cabot-search huggingface dataset:
Assessment of two prognostic risk group methods to predict outcomes with docetaxel-based therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: G. R. Pond, A. J. Armstrong, B. A. Wood, M. Brookes, L. H. Leopold, J. M. Burke, J. R. Caton, M. T. Fleming, G. Sonpavde
Journal: Journal of Clinical Oncology (2011)

185 Background: Threeprognosticrisk groups have been identified in men with mCRPC (good [GR]/intermediate [IR]/poor [PR]) based on 0-1, 2 or 3-4 factors (visceral disease, pain, anemia, bone scan progression). Prostate Cancer Working Group (PCWG)-2 defines clinical subtypes with visceral disease, bone metastases ± nodal metastases and nodal disease only. The prognostic ability of risk grouping or PCWG2 subtypes was evaluated in a large, independent phase II trial. Methods: A randomized phase IItrial of 221 men with mCRPC that received docetaxel-prednisone (DP) + AT-101 (Bcl-2 inhibitor) or DP + placebo was retrospectively analyzed using Cox regression and χ 2 tests. Additional outcomes, tests and measures of discriminatory ability were assessed and will be presented. Patients from both groups were combined for analysis, as no significant differences in outcomes were observed. Results: 93, 81 and 38 men had GR, IR and PR disease. GR men were more likely than IR/PR men to be ECOG-PS 0 (48%, 27%, 21%) and had a lower median baseline PSA (63, 85, 193 ng/ml). Significant differences between risk groups were observed for progression-free survival (PFS, p=0.009) and overall survival (OS, p&lt;0.001), while PCWG2 subtypes did not discriminate for these outcomes. Both risk groups and PCWG2 subtypes inconsistently predicted PSA declines (table). Conclusions: Prognostic risk groups significantly distinguished between outcomes in men with mCRPC receiving DP-based therapy, while PCWG2 subtypes did not. Risk groups may enhance stratification of patients in randomized trials and enable tailored drug development. Prognostic models that incorporate tumor molecular features may improve discriminatory ability. [Table: see text] [Table: see text]
BMET-03SOLID TUMORS EXPLOIT INNATE IMMUNITY TO GENERATE LEPTOMENINGEAL METASTASES
Authors: Adrienne Boire, Yilong Zou, Leni Jacob, Lisa DeAngelis, Joan Massagué
Journal: Neuro-Oncology (2015)

Leptomeningeal metastasis represents a rare but fatal outcome of disseminated cancer. Although much has been learned through observational studies, retrospective analyses and case reports, understanding of the molecular mechanisms underlying this complication has lagged behind that of other metastatic sites. To this end, we have created interrogable mouse models of breast and lung cancer that separate the molecular characteristics required for cancer cell access to the leptomeningeal space from those characteristics needed for cancer cell survival within the CSF. These models are both histologically and transcriptomally distinct from parenchymal metastases. Transcriptomal profiling of these diverse models representing breast and lung cancers in both xenograft and syngeneic systems has identified a distinct set of genes or “signature” differentially expressed by cells competent to seed and grow within the leptomeninges. This signature provides evidence that circulating cancer cells exploit the innate immune system to bypass the blood-CSF-barrier and gain access to and survive within the spinal fluid. These gene products are detectable in CSF from patients with cytology- or MRI-proven leptomeningeal metastasis. Genetic or pharmacologic blockade of select genes within this signature inhibits seeding of the leptomeninges by circulating tumor cells and inhibits growth of cancer cells within this space. This work demonstrates that leptomeningeal metastases are the result of distinct alterations in gene expression apart from those characterizing parenchymal metastases. Further, these models provide evidence that diverse primary tumors employ a conserved mechanism to arrive and survive within the CSF. Finally, this conserved gene signature shows great promise as a therapeutic target for this morbid complication of cancer.
Doctors in Pakistan call for workers deported from the UAE to be screened for HIV
Authors: Ashfaq Yusufzai
Journal: BMJ (2016)

Doctors and health agencies in Pakistan have called on the government to introduce screening for HIV for people being deported from the United Arab Emirates (UAE) to protect others from infection.

Pakistani authorities have reported concerns over the spread of the virus by people who are deported from the UAE after testing positive for HIV and who keep their status secret because of social taboos.

“As there are no …
Heparin-PF4 Antibodies Are Frequent after Vascular Surgery, but Not a Frequent Cause of Graft Thrombosis or Thrombocytopenia.
Authors: Tamas Alexy, Sony Tucker, Soames Boyle, Leanne Rochanda, Douglas Hood, Vincent L. Rowe, Fred A. Weaver, Howard A. Liebman
Journal: Blood (2006)
Effect of imatinib (IM) discontinuation after seven years of complete remission in a patient with metastatic GIST: A case report.
Authors: D. Pink, A. Reichardt, D. Schoeler, P. Reichardt
Journal: Journal of Clinical Oncology (2011)

e20534 Background: In a randomized trial it was shown that IM interruption results in an increased risk of disease progression (PD) after 1, 3, or 5 years (yrs) of therapy. Therefore, according to current guidelines, patients (pts) with advanced or metastatic GIST should be treated with imatinib until PD or intolerance of therapy. However, due to individual reasons, pts in long-term complete remission sometimes (CR) raise the question, if their IM can be discontinuated safely. Methods: We report a case of a patient with metastatic GIST, who was in CR with IM for 7 yrs, and developed rapid disease progression after IM interruption. Results: In an 80 yrs old woman a high-risk GIST of the colon was resected in 2001. After 5 months peritoneal metastases (pm) were detected with CT-scan and verified by biopsy. IM was started at a dose of 400mg daily. Partial remission (PR) of all pm was achieved after 6 weeks and a CR was documented after 3 months of therapy. With the age of 88 yrs and being in CR for more than 7 years the patient decided to stop therapy with IM due to multiple reasons (age, other diseases, chronic renal failure). After only 5 months without IM dramatic progression of GIST was found with multiple new pm up to 5cm. After extensive discussion the patient accepted reintroduction of imatinib treatment at 400 mg per day. One year later the patient is well and in continuos PR. Conclusions: Metastatic GIST is a lethal disease and IM is generally well tolerated. Therapy with IM should not be interrupted in non progressing pts without limitating side effects even after long-term complete remission and in old age.
B Precursor ALL Subset with Aberrant CD2 Expression and a Specific Predisposition to Early Monocytic Transdifferentiation
Authors: Ester Mejstrikova, Lucie Slamova, Eva Fronkova, Jan Zuna, Jean-Pierre Bourquin, Elena Vodickova, Katerina Muzikova, Zuzana Zemanova, Vendula Pelkova, Frederik Van Delft, Tomas Kalina, Karel Fiser, Petr Smisek, Jan Trka, Jan Stary, Ondrej Hrusak
Journal: Blood (2010)
Poly (ADP-ribose) polymerase-1 (PARP) expression in triple-negative breast cancer.
Authors: P. Possanzini, M. O. Biasi, C. Fumagalli, M. Barberis, M. Barile, B. Bonanni, G. Viale
Journal: Journal of Clinical Oncology (2011)

1114 Background: Triple-negative breast cancer (TNBC) can affect germline BRCA 1 mutation carriers or BRCA1 wild-type patients; in both cases they lack expression of the biological markers used to select tailored therapy. According to BRCA1 status, tumour regression, relapse and resistance to therapy have different rates and are related to the ability of tumour cell to repair therapy induced DNA damage. In carriers of BRCA-1 mutations, homologous recombination mechanisms are usually inhibited; moreover base excision repair, a single strand repair mechanism in which PARP plays a pivotal role, can be down-regulated by PARP inhibitors. These drugs are actually considered potentially useful in carriers of BRCA-1 mutations. The goal of this study was the evaluation of quantitative expression of PARP1 in patients with BRCA-1 mutation compared to patients with BRCA1 wild type developing TNBC. Methods: We studied 25 TNBC –BRCA wild-type and 20 TNBC-BRCA1 mutated patients. RNA was extracted from unfixed and formalin-fixed and paraffin embedded (FFPE) tumor specimens in RNase-free laboratory conditions. PARP1 relative quantity (RQ) was evaluated by a quantitative RT-PCR assay. Results: The levels of PARP1 expression from FFPE specimens were confirmed on unfixed specimens. In TNBC, RQ ranged from 3,29 to 34,39; in BRCA1-mutated RQ ranged from 0 to 140. Although different RQ range, the two groups show similar distribution and RQ values overlap on log10 scale graph. Student’s t test (BRCA1 mut /BRCA1 wt): Number of samples 20/25; Media 27,4/36,5; Standard DEV 12,51/29,7; degrees of freedom 43; p Value 0,206 t: 1,28. Conclusions: The expression of PARP1 was similar and heterogeneous in the two groups. These preliminary observations could favour the hypothesis of offering PARP inhibitors to TNBC as it is proposed in BRCA1 mutated patients. This assay could be used prospectively as a predictive parameter for response to PARP1 inhibitor therapy.
437. A Light-Producing Model of Infection-Related Preterm Birth
Authors: Natalie Suff, Rajvinder Karda, Dany Perocheau, Juliette M. Delhove, Tristan R. McKay, Mark Tangney, Suzanne M.K. Buckley, Donald Peebles, Simon N. Waddington
Journal: Molecular Therapy (2016)

Background: Preterm birth is increasing in incidence and current therapies are relatively ineffective. It is responsible for >1million neonatal deaths per annum worldwide and long term complications in survivors. Approximately 50% of PTBs are preceded by microbial invasion of the intrauterine space; current clinical management centres on diagnosis of intrauterine bacterial presence by identifying the resultant inflammatory response. To investigate the relationship between intrauterine bacterial presence and inflammation we developed two separate gene technology approaches: 1. Intravaginal bioluminescent bacteria to measure bacterial ascent into the uterus which mimics the ascending vaginal infection seen in preterm birth. 2. Lentiviral gene transfer of an NFKB activated luciferase reporter construct to allow bioluminescent imaging of the subsequent systemic NFKB response. Methods: An NFkB response element was cloned into a lentivirus vector upstream of the genes encoding a codon-optimised firefly luciferase. High titred virus was injected intravenously at birth to neonatal female C57BL/6 J-Tyrc-2J mice to achieve luciferase expression predominantly in the liver (to monitor systemic inflammatory response). These mice received Escherichia coli (non-pathogenic K-12, MG1655 with integrated luxABCDE operon) intra-vaginally once reaching adulthood and intraperitoneal lipopolysaccharide (LPS) three weeks later. Luciferase expression was monitored by whole body bioluminescence imaging. Local inflammation was determined using H&E, ICAM-1 (Intracellular adhesion molecule 1) and Ly6g immunohistochemistry and enzyme-linked immunosorbent assays for serum and uterine TNF-α and IL1-β cytokines. Results: Bioluminescent imaging revealed that C57BL/6 J-Tyrc-2J mice were the most susceptible mice breeds for modelling of ascending vaginal infection with E. coli luxABCDE operon. Intraperitoneal LPS induced an NF-KB response in the liver by biosensing (p<0.01), however intravaginal E. coli administration induced no response. There was evidence of uterine inflammation with an upregulation of ICAM-1 and neutrophils. Conclusion: Although it is possible to detect LPS-induced NFKB inflammation in the liver by biosensing, ascending vaginal infection induced no response. This highlights the clinical challenge of identifying bacterial presence, confined to the uterus, using systemic markers. This model can be used to test new treatments for the prevention of PTB.
T-Cell Lymphoma: Recent Advances in Characterization and New Opportunities for Treatment
Authors: Carla Casulo, Owen O’Connor, Andrei Shustov, Michelle Fanale, Jonathan W. Friedberg, John P. Leonard, Brad S. Kahl, Richard F. Little, Lauren Pinter-Brown, Ranjani Advani, Steven Horwitz
Journal: JNCI Journal of the National Cancer Institute (2016)

Peripheral T-cell lymphomas (PTCLs) are uncommon, heterogeneous, and aggressive non-Hodgkin's lymphomas. Despite progress in the last several years resulting in a deeper understanding of PTCL biology and pathogenesis, there is currently no accepted single standard of care for newly diagnosed patients, and for those with relapsed or refractory disease, prognosis is dismal. The National Cancer Institute convened a Clinical Trials Planning Meeting to advance the national clinical trial agenda in lymphoma. The objective was to identify unmet needs specific to five major lymphoma subtypes and develop strategies to address them. This consensus statement reviews recent advances in the molecular and genetic characterization of PTCL that may inform novel treatments, proposes strategies to test novel therapies in the relapsed setting with the hopes of rapid advancement into frontline trials, and underscores the need for the identification and development of active and biologically rational therapies to cure PTCL at higher rates, with iterative biomarker evaluation.
Abstract 3586: The use of kinome profiling to determine potential resistance pathways in pancreatic cancer cells treated with PIM kinase inhibitors
Authors: Vandana Singh, Brittany Nixon, T.S. Karim Gilbert, Steve Warner, David Bearss, Lee M. Graves, Antonio T. Baines
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent cancer of the pancreas with a 5-year survival rate of 6%, making it the 4th most common cause of cancer deaths in the United States. One of the challenges related to this cancer is the issue of chemoresistance. Chemoresistance renders most drugs ineffective in the treatment of PDAC, including kinase inhibitors and the chemotherapeutic drug gemcitabine. PIM (Proviral Integration site for the Moloney murine leukemia virus) kinases are a family of proteins shown to play an important role in the chemoresistance of many cancers, including pancreatic cancer. PIMs act downstream of the JAK-STAT cytokine signaling pathway and phosphorylate substrates involved in numerous cell functions including cell cycle progression and apoptosis. One objective of our research was to determine the role of PIM kinases on transformed phenotypes of PDAC cells. We were able to demonstrate that the PIM kinase inhibitor SGI-1776 and TP-3654, a second generation PIM kinase inhibitor, were able to inhibit growth in cell viability assay. Also, the PIM inhibitors were able to decrease various phenotypes such as anchorage-dependent and anchorage-independent growth in MIA PaCa-2 and PANC-1 cells. A second objective was to determine if PIM kinase inhibitors could reduce chemoresistance in PDAC cells. PIM inhibitors in combination with gemcitabine decreased cell viability in PDAC cells significantly more than when administered separately. To investigate resistance pathways activated in PDAC cells after treatment with PIM kinase inhibitors, we applied multiplexed inhibitor beads (MIBs) mass spectrometry (MS) to profile the kinome. We observed numerous kinases that were downregulated or upregulated after treatment. One of the kinases upregulated was IKKα, a key kinase in the anti-apoptotic NF-κB signaling pathway. Our results suggest that PIM kinases are an important target for cell growth and chemoresistance in pancreatic cancer. Also, these results suggest that treating PDAC cells with a PIM inhibitor simultaneously with an IKK inhibitor might prevent the effects of resistance pathways. Overall, our studies demonstrate that kinome profiling is an effective strategy to identify cellular responses to PIM kinase inhibitors as well as other drugs for treating pancreatic and other cancers. Citation Format: Vandana Singh, Brittany Nixon, T.S. Karim Gilbert, Steve Warner, David Bearss, Lee M. Graves, Antonio T. Baines. The use of kinome profiling to determine potential resistance pathways in pancreatic cancer cells treated with PIM kinase inhibitors. [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 3586. doi:10.1158/1538-7445.AM2015-3586
Predictive value of human papillomavirus (HPV) 16 in situ hybridization (ISH) and p16 immunohistochemistry (IHC) for HPV oncogene expression in paraffin-embedded oropharynx squamous cell carcinoma (OPSCC).
Authors: M. L. Gillison, R. Jordan, M. Lingen, B. Perez-Ordonez, X. He, R. Pickard, A. Inman, M. Koluder, B. Jiang, P. Wakely, W. Xiao
Journal: Journal of Clinical Oncology (2011)

5512 Background: Tumor HPV status is a strong, independent predictor of OPSCC survival and increasingly used for therapeutic decision making. Methods for classification are variable and not standardized. Here we validate our methods for HPV classification used in past and ongoing cooperative group trials (ECOG and RTOG). Methods: Consecutive OPSCC diagnosed from 2000-2009 were obtained from four referral centers. Tumor DNA and RNA were extracted and categorized as evaluable or inevaluable by DNA detection (ERV3) and mRNA expression (RPLPO) of control genes by quantitative (q) PCR. Presence of 18 high-risk HPV types was detected by consensus primer PCR and line-blot hybridization (Inno-Lipa) followed by viral load measurement and HPV oncogene expression (E6/7) analysis by HPV type-specific q RT-PCR. P16 expression was detected by IHC and HPV16 by ISH and sensitivity (S), specificity (SP), positive (PPV) and negative predictive value (NPV) were compared to gold standard HPVE6/7 oncogene expression. Assay interpretation was performed by three masked pathologists. Inter-assay and inter-rater agreement was evaluated by kappa statistic. Sample size provided 80% power for Cohen’s kappa of 0.8 or higher among three raters. Results: 235/237 OPSCC were evaluable, 183 (78%) HPV DNA-positive, and 158 (67%) HPVE6/7 expression positive (16, 92%; 18, 3%; 33, 3%; 35, 1%; 58, 1%) with median viral load of 15.7 copies/cell, E6/7 expression of 210 copies/1,000 RPLPO, p16 expression 46.7 vs. 2.9 copies/1000 RPLPO for HPVE6/7-negative, p<0.001. S/SP/PPV/NPV of HPV16 ISH for HPV16E6/7 was 91/91/94/86 and for p16 for HPVE6/7 was 97/82/92/93 and for combined testing was 84/97/99/75. P16 IHC and HPV16 ISH had very good agreement (kappa=0.64) with HPVE6/7 expression detected in 99%/63%/50%/3% of ++/+-/-+/-- cases, respectively. Inter-rater agreement was excellent for p16 (kappa=0.95-.98) and HPV16 ISH (kappa.0.83-.91). Conclusions: HPV16 ISH and p16 IHC have excellent assay performance. However, if results are used for therapy “deintensification” among HPV-positive cases, combined testing provides higher SP and PPV.
Proteomic analysis of TLR7 expression and clinical correlation in prostate carcinomas compared with prostatic benign lesions.
Authors: R. Aragon-Franco, H. Rosas-Hernandez, G. Garrido-Sanchez, H. Astudillo
Journal: Journal of Clinical Oncology (2011)

e15195 Background: Toll-Like receptors (TLRs) induce cytokines expression and type I interferon and other immune molecules, which drive an inflammatory response and activate the adaptive immune system. Nowadays TLRs have an extraordinary importance in cancer research because of their role in tumor progression. The aim of this study was to investigate the expression and clinical relevance of TLR7 in prostate cancer biopsies. Methods: The expression level of TLR7 was analyzed on prostate tumors from 15 patients and 19 patients with diagnostic of benign prostatic hyperplasia as control tissues. The analyses were performed by immunohistochemistry on tissue arrays and a microscopy video-capture system (Axiovert 200M, Karl Zeiss, Germany) was used to evaluate the protein expression using a software KS-300 V3.0. Statistical analysis was performed using T Student. Results: Cancerous cells showed lower expression levels of TLR7 compared with controls (benign prostatic hyperplasia). Samples of carcinomas exhibited a significant decrease in the protein levels of TLR7 (304.67 ODU; SD+/-85.55 ODU) and benign prostatic hyperplasia lesions showed higher expression levels (478.58 ODU; SD+/-131.07 ODU). Statistical analysis showed a significant correlation with a p=0.0001 by T-Student. In addition, the tumors that showed lower TLR7 protein expression levels were significantly associated with a worse clinical prognosis. Conclusions: A lower TLR7 protein expression is associated with prostate cancer with worse prognosis and the role of TLR7 receptors in the biology of malignancy merits study in a larger sample study. These kinds of result suggest that in future therapeutic strategies to boost TLR7 may be of interest in the therapeutic area of prostate cancer.
Abstract 5544: Attempts to synthesize 5,7-dihydroxy-3H-1,2-dithiolo[4,3-d]- pyrimidine, M-47, a potential new treatment for drug- resistant breast cancer
Authors: Canio J. Marasco, Joseph A. Dunn, Paula J. Pera, Alexander E. Macubbin
Journal: Cancer Research (2015)

Abstract M-47, 5,7-Dihydroxy-3H-1,2-dithiolo[4,3-d]pyrimidine, represents a novel class of antineoplastic agents both in structure and apparent mechanism of action. The synthesis of M-47 has been shown to be problematic. Mass spectroscopy and HPLC suggest the presence of certain oxidative byproducts in minor quantities along with the desired analog. Repeated efforts to purify M-47 via crystallization, extraction, chemical modification, and various forms of chromatography have failed. Although enrichment of the sample in excess of 90% is possible, absolute purity has not been achieved. Despite the presence of minor impurities this analog was tested against a variety of cancer cell lines in vitro. Interestingly, M-47 displayed equipotent activity against certain breast cancer lines and their multidrug resistant progeny Furthermore, in vitro testing of various ratios of M-47 with its oxidative byproducts indicated that they possessed similar IC50's suggesting that cellular oxidation of M-47 might be a necessary step in its cytotoxic pathway. The profound activity of M-47, especially against drug-resistant tumor cells, warrants further investigation into the chemistry of these compounds, their biological activity and their possible mechanism of action. Note: This abstract was not presented at the meeting. Citation Format: Canio J. Marasco, Joseph A. Dunn, Paula J. Pera, Alexander E. Macubbin. Attempts to synthesize 5,7-dihydroxy-3H-1,2-dithiolo[4,3-d]- pyrimidine, M-47, a potential new treatment for drug- resistant breast cancer. [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 5544. doi:10.1158/1538-7445.AM2015-5544
The NF-κB Pathway Is Targeted by Multiple Genetic Lesions In Splenic Marginal Zone Lymphoma
Authors: Davide Rossi, Daniela Capello, Silvia Rasi, Valeria Spina, Marco Fangazio, Riccardo Bruna, Silvia Franceschetti, Stefania Cresta, Luca Arcaini, Luca Baldini, Jean Soulier, Catherine Thieblemont, Roberto Marasca, Fabio Facchetti, Andrea Rinaldi, Francesco Bertoni, Gianluca Gaidano
Journal: Blood (2010)
A Predictive Model for the Development of High-Responding Inhibitor In Children with Severe and Moderate Hemophilia A- Results of a Multicenter Cohort Study
Authors: Susanne Holzhauer, Christoph Bidlingmaier, Carmen Escuriola Ettingshausen, Susan Halimeh, Alfonso Iorio, Gili Kenet, Brigitte Pautard, Ulrike Nowak-Gottl
Journal: Blood (2010)