tbuckley/cabot-search huggingface dataset:
KEYNOTE-057: Phase 2 study of pembrolizumab for patients (pts) with Bacillus Calmette Guerin (BCG)-unresponsive, high-risk non-muscle-invasive bladder cancer (NMIBC).
Authors: Ashish M. Kamat, Joaquim Bellmunt, Toni K. Choueiri, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo F. Perini, Arlene O. Siefker-Radtke, Guru Sonpavde, Ronald De Wit, Alfred Witjes, Stephen Michael Keefe, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2016)

TPS4576 Background: The majority of pts presenting with bladder cancer ( > 70,000 cases/y in the United States) have NMIBC. Despite standard of care therapy with transurethral resection of bladder tumor [TURBT] and BCG administration, a large percentage of pts will have disease recurrence/progression. PD-L1 is widely expressed in urothelial tumors. Pembrolizumab, an anti–PD-1 antibody, blocks the interaction of PD-1 and its ligands, PD-L1 and PD-L2. KEYNOTE-057 (NCT02625961) is a single-arm, open-label, phase 2 study to evaluate pembrolizumab in pts with high-risk NMIBC unresponsive to BCG. Methods: Key inclusion criteria include age ≥ 18 y; BCG-unresponsive NMIBC (high-grade Ta, T1, and/or carcinoma in situ [CIS] despite adequate BCG treatment); ineligible for/or declines radical cystectomy; ECOG PS 0-2. Pts must have undergone ≥ 2 cystoscopic procedures with the most recent ≤ 8 wk of study start, including complete TURBT (tissue sample must be available). Pts will receive pembrolizumab 200 mg Q3W for 24 mo or until disease recurrence or progression, unacceptable toxicity, pt withdrawal, or investigator decision. Pts will be placed into cohorts by presence (cohort A) or absence (cohort B) of CIS based on tissue pathology at screening. Tumors will be evaluated using cystoscopy and urine cytology every 12 wk for the first 2 y, every 24 wks for the next 2 y, and every 52 wk thereafter. CT imaging will be used to assess for upper tract and metastatic or nodal disease. At 18 mo, pts with no evidence of disease may discontinue treatment. Pts with low-grade Ta recurrence will be allowed to undergo repeat TURBT and remain on treatment; low-grade recurrence will not be considered treatment failure. AEs will be monitored throughout the study and for 30 days (90 days for SAEs and ECIs) after study end and graded per CTCAE v4.0. The primary end points are complete response for pts with CIS (cohort A) and disease-free survival for those without CIS (cohort B); secondary end points include progression-free survival, overall survival, duration of response, and PD-L1 expression in relation to clinical outcome. Enrollment is ongoing and will continue until ~260 pts are enrolled. Clinical trial information: NCT02625961.
Abstract 72: Therapeutic compound discovery targeting a recurrent glioblastoma (GBM) phenotype using LINCS compounds via QUADrATiC analyses
Authors: Shahnaz T. Al Rashid, Paul O’Reilly, Philip D. Dunne, Matthew Alderdice, Thomas J. Flannery, Kevin M. Prise, Shu-Dong Zhang, Darragh G. McArt
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM) is the most prevalent and aggressive of malignant primary brain tumours. Despite multi-modal therapy, including surgical resection, radiotherapy and chemotherapy, GBM continues to be uniformly lethal, with a median survival of 12-18 months from the time of diagnosis. The resistance to therapy and ultimate recurrence is thought to originate from a sub-population of cells residing in the initial tumour, identified as glioma-initiating or glioma-stem cells (GSC). These GSC have been shown to be intrinsically more invasive, with enhanced repair and drug-efflux pathways mediating resistance to chemo-radiation therapies. The purpose of this study was to use and validate a novel connectivity mapping procedure to identify candidate compounds targeting therapy-resistant and recurrent GBM. This procedure was developed by O’Reilly and colleagues (“QUADrATiC: A Scalable Approach to Repurposing FDA-approved therapeutics”, under review in Bioinformatics), and in this study, was performed on publicly available NCBI GEO microarray datasets. Based on the cancer stem cell theory whereby the resistant GSCs repopulate and are enriched in recurrent tumours, primary and recurrent GBM gene expression profiles were compared and the connections between the identified gene lists and drug responses were mapped. To validate that this connectivity mapping procedure is reliable at identifying effective treatments to target therapeutic resistance and recurrence, we tested one of the top ten compounds identified, rosiglitazone (rosi), a ligand of the peroxisome proliferator activated receptor gamma (PPARγ). The efficacy of rosi alone and in combination with the current standard of care therapies, temozolomide and radiation, at killing GSC was assessed in vitro using the clonogenic survival assay. Our data indicated that rosi significantly reduced survival of both non-stem glioma cells and GSC, alone and in combination with radiation and temozolomide. The p53 pathway was identified as a pathway by which rosi may induce permanent cell cycle arrest and cell death. Further work is ongoing to fully elucidate the downstream mechanisms of cell death. This work is proof-of-principle that the current connectivity mapping procedure can be instrumental in identifying more targeted therapeutic interventions for GBM resistance and prevent recurrence. Citation Format: Shahnaz T. Al Rashid, Paul O’Reilly, Philip D. Dunne, Matthew Alderdice, Thomas J. Flannery, Kevin M. Prise, Shu-Dong Zhang, Darragh G. McArt. Therapeutic compound discovery targeting a recurrent glioblastoma (GBM) phenotype using LINCS compounds via QUADrATiC analyses. [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 72.
Abstract 3075: Nuclear export inhibitor selinexor (KPT-330) demonstrates anti-tumor efficacy alone and in combination with chemotherapy in multiple breast cancer models
Authors: Natalia Paez Arango, Kurt Evans, Ming Zhao, Erkan Yuca, Stephen Scott, Charissa Kim, Aung Naing, Funda Meric-Bernstam
Journal: Cancer Research (2016)

Abstract Background: The nuclear exporter XPO1 (Exportin1 or CRM1), mediates the transport of over 200 proteins, including several tumor suppressors. For this reason, XPO1 is being pursued as a promising target for cancer therapy options. Selinexor (KPT-330), a selective inhibitor of nuclear export, is an oral agent that has been shown to inhibit XPO1 and is currently in phase 2 trials for hematologic and solid tumors. We sought to determine the antitumor effect of selinexor in breast cancer cells in vitro and in vivo Methods: We studied the effects of selinexor in vitro using cell proliferation assays; the half maximal inhibitory concentration (IC50) was calculated using isobologram curves after 3 days of treatment. We also tested the effects in combination with chemotherapy and calculated the combination index by the method of Chou and Talalay. In vivo efficacy was tested in triple negative breast cancer (TNBC) patient derived xenografts (PDXs) with varying levels of paclitaxel sensitivity, as single agent and in combination therapy. T/C ratio was calculated using the formula: [(median tumor volume of treated group)/(median tumor volume of control group) x 100] Results: Selinexor treatment inhibited growth of 12 breast cancer cell lines representing different subtypes (TNBC as well as ER+, HER+) with a median IC50 of 375nM (range 3-750nM). Selinexor significantly reduced tumor growth in vivo in 4 of 5 different TNBC PDX models (with varying status of TP53 and PIK3CA, and gene expression subtypes), with a median T/C score of 48% (range 34-59%) In Multiple TNBC cell lines, selinexor was synergistic with paclitaxel, carboplatin, eribulin and doxorubicin in vitro. In vivo, selinexor in combination with paclitaxel or eribulin had greater antitumor efficacy than either agent alone. Conclusions: Collectively these findings strongly suggest that selinexor is a promising therapeutic option for breast cancer. Citation Format: Natalia Paez Arango, Kurt Evans, Ming Zhao, Erkan Yuca, Stephen Scott, Charissa Kim, Aung Naing, Funda Meric-Bernstam. Nuclear export inhibitor selinexor (KPT-330) demonstrates anti-tumor efficacy alone and in combination with chemotherapy in multiple breast cancer models. [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 3075.
Abstract 1617: RUNX3 inhibits metastasis and angiogenesis in colorectal cancer
Authors: Bo Ram Kim, Jung Lim Kim, Yoo Jin Na, Seong Hye Park, Sun Il Lee, Sanghee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Dae-Hee Lee, Byung-Wook Min, Sang Cheul Oh
Journal: Cancer Research (2016)

Abstract Recent studies proved that an inactivation of RUNX3 (runt-related transcription factor-3) expression is highly associated with lymph node metastasis and poor prognosis in various cancer types. However, the mechanism of RUNX3-mediated suppression of tumor metastasis remains unclear. Herein, we aimed to clarify the effect of RUNX3 on metastasis and angiogenesis in colorectal cancer (CRC). First, we found that the reduction of expression of RUNX3 in CRC tissues when compared with tumor adjacent normal colon tissues, as indicated by reduced RUNX3 staining, was significantly correlated with TNM stage. Second, we demonstrated that RUNX3 overexpression inhibited CRC cell migration and invasion resulting from the elevated upregulation of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) expression. In contrast, the knockdown of RUNX3 reduced the inhibition of migration and invasion of CRC cells. Last, Vascular endothelial growth factor(VEGF) is an inducer of angiogenesis and lymphangiogenesis. We found that restoration of RUNX3 decreased vascular endothelial growth factor (VEGF) secretion and suppressed endothelial cell growth and tube formation in CRC cells. Taken together, our data demonstrated that RUNX3 may provide insights into the development of RUNX3 for CRC metastasis diagnostics and therapeutics. Citation Format: Bo Ram Kim, Jung Lim Kim, Yoo Jin Na, Seong Hye Park, Sun Il Lee, Sanghee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Dae-Hee Lee, Byung-Wook Min, Sang Cheul Oh. RUNX3 inhibits metastasis and angiogenesis in colorectal cancer. [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 1617.
<i>In Utero</i> Exposure to Benzo[ <i>a</i> ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice
Authors: Matthew J. Meier, Jason M. O’Brien, Marc A. Beal, Beverly Allan, Carole L. Yauk, Francesco Marchetti
Journal: Environmental Health Perspectives (2016)

Background:Mosaicism, the presence of genetically distinct cell populations within an organism, has emerged as an important contributor to disease. Mutational events occurring during embryonic development can cause mosaicism in any tissue, but the influence of environmental factors on levels of mosaicism is unclear.Objectives:We investigated whether in utero exposure to the widespread environmental mutagen benzo[a]pyrene (BaP) has an impact on the burden and distribution of mutations in adult mice.Methods:We used the Muta™Mouse transgenic rodent model to quantify and characterize mutations in the offspring of pregnant mice exposed to BaP during postconception days 7 through 16, covering the major period of organogenesis in mice. Next-generation DNA sequencing was then used to determine the spectrum of mutations induced in adult mice that were exposed to BaP during fetal development.Results:Mutation frequency was significantly increased in the bone marrow, liver, brain, and sperm of first filial generation (F1) males. Developing embryos accumulated more mutations and exhibited higher proportions of mosaicism than exposed adults, particularly in the brain. Decreased sperm count and motility revealed additional negative impacts on the reproductive function of F1 males.Conclusion:In utero exposure to environmental mutagens contributes to somatic and germline mosaicism, permanently affecting both the genetic health of the F1 and the population gene pool.Citation:Meier MJ, O'Brien JM, Beal MA, Allan B, Yauk CL, Marchetti F. 2017. In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ Health Perspect 125:82–88; http://dx.doi.org/10.1289/EHP211
Global Genomic Status At Diagnosis Informs Clinical Outcome in B-Chronic Lymphocytic Leukemia: Stable Versus Progressive Disease
Authors: Daniel L. Van Dyke, Jeannette G Rustin, Stephanie A. Smoley, Jeanette Eckel Passow, Ruchi G. Sharma, Esteban Braggio, Tait D. Shanafelt, Neil Kay
Journal: Blood (2011)
Abstract 2325: Immune checkpoint(s) expression in AML patients enrolled in a phase 1-2 study with guadecitabine
Authors: Carolina Fazio, Alessia Covre, Maria Lofiego, Pietro Taverna, Mohammad Azab, James N. Lowder, Sandra Coral, Michele Maio
Journal: Cancer Research (2016)

Abstract Immune checkpoint(s) blockade is becoming the therapeutic mainstay in melanoma and lung cancer. Based on these important clinical achievements, immunotherapy with immunomodulating monoclonal antibodies (mAb) is being explored as a new therapeutic modality in most human malignancies, either alone or in combination with other immunomodulating agents. We have provided extensive evidence that the second generation DNA hypomethylating agent (DHA), guadecitabine (SGI-110), plays a promising role in potentiating the immunogenicity and the immune recognition of human malignancies through the up-regulation of the expression of different immune molecules on cancer cells. These findings led us to hypothesize that DHA could represent ideal partners for immune checkpoint(s) blocking agents to improve their therapeutic efficacy. Here, we studied the expression of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and 2 (PD-L2), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) in peripheral blood mononuclear cells of acute myeloid leukemia (AML) patients (N = 23), enrolled in a phase 1-2 study with guadecitabine. Patients included in this preliminary analysis were selected based on their responsiveness to therapy. Quantitative RT-PCR analyses showed a constitutive expression (gene/β-actin molecules &amp;gt;7.5E-05) of PD1, PD-L1, PD-L2 and CTLA-4 in 82.6%, 100%, 47.8% and 8.7% patients, respectively. Guadecitabine therapy up-regulated (≥2 fold) the expression of PD1, PD-L1, PD-L2 and CTLA-4 in 57.9%, 56.5%, 18.2% and 0% patients, respectively, at any of the time-points investigated during treatment. De novo expression of PD1, PD-L2 and CTLA-4 was observed in 100%, 41.6% and 38.1% of the immune checkpoint(s)-negative patients, respectively. Though preliminary, these results further support the strong link between epigenetics/DNA methylation and immune response, in cancer patients, and strengthen the therapeutic potential of epigenetic immunomodulation, with “consolidated” and emerging immune checkpoint(s) blocking mAb. Citation Format: Carolina Fazio, Alessia Covre, Maria Lofiego, Pietro Taverna, Mohammad Azab, James N. Lowder, Sandra Coral, Michele Maio. Immune checkpoint(s) expression in AML patients enrolled in a phase 1-2 study with guadecitabine. [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 2325.
Chromothripsis-Mediated Structural Variations and Clonal Evolution In Recurrent Childhood High Hyperdiploid Acute Lymphoblastic Leukemia
Authors: Cai Chen, Christoph Bartenhagen, Michael Gombert, Vera Okpanyi, Vera Binder, Andrea Teigler-Schlegel, Jutta Bradtke, Silja Roettgers, Jochen Harbott, Sebastian Ginzel, Ralf Thiele, Martin Dugas, Jianda Hu, Arndt Borkhardt, Ute Fischer
Journal: Blood (2013)
Abstract 4422: Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation
Authors: Yu Ran Lee, Hee Kyoung Joo, Ki Mo Kim, Byeong Hwa Jeon, Sunga Choi
Journal: Cancer Research (2016)

Abstract The present study evaluated the mechanism of apoptosis caused by posttranslational modification, hyperacetylation in triple-negative breast cancer (TNBC) cells. We previously showed that trichostatin A (TSA) induced secretion of acetylated apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1). This is the first report showing that Ac-APE1/Ref-1 initiates apoptosis in TNBC cells by binding to the receptor for advanced glycation end products (RAGE). The functional significance of secreted Ac-APE1/Ref-1 was studied by induction of intracellular hyperacetylation through co-treatment with acetylsalicylic acid and TSA in MDA-MB-231 cells. In response to hyperacetylation, secretion of Ac-APE1/Ref-1 in vesicles was observed, resulting in significantly decreased cell viability and induction of apoptosis with increased expression of RAGE. The hyperacetylation-induced apoptosis was similar in two other TNBC cell lines: BT-459 and MDA-MB-468. Therefore, hyperacetylation may be a therapeutic target for treatment of TNBCs. This study introduces a novel paradigm whereby posttranslational modification induces apoptotic cell death in breast cancer cells resistant to standard chemotherapeutic agents through secretion of auto- or paracrine molecules such as Ac-APE1/Ref-1. Citation Format: Yu Ran Lee, Hee Kyoung Joo, Ki Mo Kim, Byeong Hwa Jeon, Sunga Choi. Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation. [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 4422.
Intravenous ferric carboxymaltose versus standard care in the management of postoperative anaemia: a prospective, open-label, randomised controlled trial
Authors: Alhossain A Khalafallah, Carl Yan, Raghad Al-Badri, Ella Robinson, Brooke E Kirkby, Emily Ingram, Zara Gray, Vinod Khelgi, Iain K Robertson, Brian P Kirkby
Journal: The Lancet Haematology (2016)
NHS “haemorrhaging money” on clinical negligence claims, defence bodies warn
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The NHS paid out £1.5bn (€1.8bn; $2bn) on clinical negligence claims in 2015-16, a rise of 27% from the previous year.

The figures, released by the NHS Litigation Authority, showed that the overall cost of settling claims rose by around £300m in 2015-16. This included an additional £176m in damage payments (a 23% rise from 2014-15) and an extra £126m in claimants’ legal costs (a 43% increase).1

The figures prompted calls for urgent legal reform from medical defence bodies amid warnings that the NHS was “haemorrhaging money” on claims.

The increased costs came despite the number of claims for clinical negligence falling slightly from 11 497 in 2014-15 to 10 965 last year.

The figures also showed that the estimated provisions for hospital clinical negligence claims almost doubled from £28.6bn in 2014-15 …
Polyadenosine diphosphate-ribose polymerase (PARP) inhibition as a means of protecting the inner ear from cisplatin (CDDP)-mediated ototoxicity without affecting antitumor efficacy in vitro.
Authors: F. Mayer, M. Mueller, E. Malenke, A. Schrattenholz, H. Kopp, H. Loewenheim
Journal: Journal of Clinical Oncology (2010)

e13501 Background: Hearing loss can be the dose limiting toxicity of CDDP. In the treatment of germ cell tumors (GCT) or adjuvant therapy of non-small cell lung cancer (NSCLC), CDDP cannot be replaced without loss of efficacy. Inhibition of PARP, an enzyme of the base excision repair pathway, is a novel anti-neoplastic principle. PARP-activation has been identified to induce cell death following inner ear trauma. We evaluated PARP-inhibition by pirenzepin as a means to protect the ear from CDDP. Methods: In an in vitro culture model, inner ears were treated continuously with 1.4 μM CDDP. Ears were obtained from heterozygous and homozygous PARP-knock out mice and wild-type controls at postnatal day 7. The number of preserved hair cell stereocilia bundles was counted by fluorescence microscopy after labeling with phalloidin. Cytotoxicity of CDDP and the effect of pirenzepin were assessed by MTS-assays and flow cytometry using the cell lines 2102EP, NT2 (both GCT) and NCI-H460 (NSCLC). Results: In wild-type mice, only 45% of the inner and 30% of the outer hair cells were preserved following CDDP-exposure compared to untreated controls. In heterozygous PARP-knock out mice, 90% and 80% of the hair cells survived CDDP exposure. The fractions of surviving hair cells in the homozygous knock out mice were 70% and 50%, respectively, the difference was significant (p<0.05). Protection of 60-80% hair cells could be achieved by pirenzepin in wild-type mice with the maximum protective effect at intermediate dose levels. Pirenzepin alone did not affect growth in any cell line. Cytotoxicity of CDDP as measured by IC50 determination in MTS assay or by flow-cytometric assessment of vital cells was not affected by pirenzepin. Conclusions: PARP-activation seems to play a relevant role in CDDP-induced ototoxicity. Thus, PARP-inhibition appears to be a promising means to protect hearing under CDDP therapy, especially since PARP-inhibition did not diminish sensitivity of GCT and NSCLC cell lines to CDDP, even though no synergistic effect could be observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ProteoSys AG ProteoSys AG