tbuckley/cabot-search huggingface dataset:
Abstract 3855: Refolded albumin inhibits IL-17B-driven pancreatic cancer migration
Authors: Chi-Ming Liang, Ching-Chun Liao, Shu-Mei Liang
Journal: Cancer Research (2016)

Abstract Folding and refolding a protein may change its physical, chemical and biological properties. Here, we used a novel protein refolding protocol to convert globular albumin into another form, namely f-albumin, with melting point 10oC higher than albumin (83oC vs 72oC). f-albumin, unlike albumin, inhibited the migration/invasion of a variety of cancer cells. Recently, anti-IL-17RB antibodies have been shown to block the IL-17B-IL17RB signaling-mediated migration/metastasis of pancreatic cancer cells via silencing multiple chemokines, notably CCL20, CXCL1, IL-8 and TFF1. We thus examined whether f-albumin is effective in blocking the stimulatory effects of IL-17B. We found that f-albumin inhibited the migration of pancreatic cancer cells (BxPC3, MIA-paca2 and Panc1) with IC50 around 0.2 μM. Although IL-17B (50 ng/ml) increased the migration of pancreatic cells, this effect of IL-17B was abolished by f-albumin (0.2 μM). The inhibitory effect of f-albumin, however, was not necessarily correlated with its inhibition of CCL20, CXCL1, IL-8 or TFF1. Additional study revealed that IL-17B increased the phosphorylation of PI3K, Akt and MAPK in pancreatic cancer cells. f-albumin modulated not only the IL-17B-mediated phosphorylation of Akt but also the IL-17B-mediated phosphorylation of MAPK in an integrin-dependent manner. These findings demonstrated that f-albumin downregulates Akt/MAPK signaling via integrin to play a braking role in the IL-17B-driven pancreatic cancer migration. Citation Format: Chi-Ming Liang, Ching-Chun Liao, Shu-Mei Liang. Refolded albumin inhibits IL-17B-driven pancreatic cancer migration. [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 3855.
Synergistic Antilymphoma Effect of Protein Kinase C Beta (PKCβ) and mTOR Inhibition in Mantle Cell Lymphoma.
Authors: Grit Hutter, Yvonne Zimmermann, Malte Rieken, Elena Hartmann, Vindi Jurinovic, Andreas Rosenwald, Marc Weinkauf, Wolfgang Hiddemann, Martin H. Dreyling
Journal: Blood (2009)
Risks and Benefits of Sex-Mismatched Hematopoietic Cell Transplantation Differ By Conditioning Intensity
Authors: Hideki Nakasone, Mats Remberger, Lu Tian, Petter Brodin, Bita Sahaf, Fang Wu, Robert Lowsky, Jonas Mattsson, Robert S. Negrin, David B. Miklos, Everett Meyer
Journal: Blood (2014)
The Acrylonitrile Analog, VJ-289 Ablates Acute Myelogenous Leukemia Blast, Progenitor and Stem Cell Populations by Inducing Tubulin Acetylation and Caspase Activation
Authors: Hongliang Zong, Narsimha Reddy Penthala, Siddhartha Sen, Sarah Brennan, Vijayakumar Sonar, Peter A. Crooks, Monica L. Guzman
Journal: Blood (2011)
Imaging mass spectrometry assists in the classification of diagnostically challenging atypical Spitzoid neoplasms
Authors: Rossitza Lazova, Erin H. Seeley, Heinz Kutzner, Richard A. Scolyer, Glynis Scott, Lorenzo Cerroni, Isabella Fried, Milena E. Kozovska, Arlene S. Rosenberg, Victor G. Prieto, Bahig M. Shehata, Megan M. Durham, Gina Henry, Jose L. Rodriguez-Peralto, Erica Riveiro-Falkenbach, Jochen T. Schaefer, Richard Danialan, Sylvie Fraitag, Sonja Vollenweider-Roten, Alireza Sepehr, Martin Sangueza, Nouf Hijazi, Yamile Corredoira, Rachel Kowal, Olga M. Harris, Francisco Bravo, Alan S. Boyd, Ralitza Gueorguieva, Richard M. Caprioli
Journal: Journal of the American Academy of Dermatology (2016)
Abstract 3990: FGFR3 mutations as novel oncogenic targets
Authors: Gabriela Martinez Cardona, Dana Gaffney, Katherine Bell, Joseph Portale, Matthew Dunworth, Matthew Lorenzi, Suso Platero, Jayaprakash Karkera
Journal: Cancer Research (2016)

Abstract Fibroblast growth factors (FGFs) are a family of homologous secreted glycoproteins involved in signaling pathways responsible for embryonic development, cell proliferation, survival, and migration. FGF activity is mediated by four transmembrane fibroblast growth factor receptors (FGFRs) which are receptor tyrosine kinases. Typically, FGF binding induces FGFR dimerization, leading to phosphorylation of the intracellular tyrosine kinase domain. This leads to downstream activation of multiple signaling pathways, including the mitogen-activated protein kinase (MAPK), PI3K/AKT, signal transducer and activator of transcription (STAT), and phospholipase-C-γ cascades. Deregulated FGFR activity, through mutations or translocations, is often associated with oncogenic events. Aberrations in FGFR genes have been observed in several tumor types including bladder, gastric, colorectal, ovarian, and hematologic cancers. To date, several FGFR3 mutations have been identified in bladder cancer. In this study, we developed a TaqMan qRT-PCR-based approach to detect four FGFR3 mutations in formalin-fixed paraffin embedded tissue (FFPET) samples. Cell lines overexpressing FGFR3 mutations were generated to determine impact on cell signaling, and sensitivity to the small-molecule pan-FGFR inhibitor JNJ-42756493. To determine the role and significance of these FGFR3 mutations in cancer, mutation expression constructs were designed and individually transfected into normal rat kidney epithelial cells. Cells harboring the FGFR3 mutations exhibited anchorage-independent growth, increased proliferation, and showed increased sensitivity to the FGFR inhibitor JNJ-42756493 in vitro compared to parental lines. These findings underline the oncogenic potential of the FGFR3 mutation genes and highlight their unique potential as predictive biomarkers in the selection of patients for FGFR-targeted therapy. Citation Format: Gabriela Martinez Cardona, Dana Gaffney, Katherine Bell, Joseph Portale, Matthew Dunworth, Matthew Lorenzi, Suso Platero, Jayaprakash Karkera. FGFR3 mutations as novel oncogenic targets. [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 3990.
A randomized, open-label, phase II study of CC-486 (oral azacitidine), alone or in combination with durvalumab (MEDI4736), in patients (pts) with myelodysplastic syndromes (MDS) unresponsive to prior parenteral azacitidine or decitabine.
Authors: Pierre Fenaux, Lewis R. Silverman, Ghulam J. Mufti, John Francis Seymour, Rami S. Komrokji, Stefan Faderl, Du Hung Lam, Michele Sharr-McMahon, C L. Beach, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2016)

TPS7078 Background: Whileparenteral hypomethylating agents (HMAs) induce hematologic response in ~50% of pts with IPSS higher-risk MDS, options are very limited for nonresponding pts who are at high risk of progression to AML and death. In a previous study of pts who had received prior HMA therapy (n = 7), extended dosing of CC-486 resulted in an overall response rate of 29%. Other promising strategies for cancer therapy are emerging, including blockade of the programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1) pathway by immune checkpoint inhibitors. In early-phase studies, durvalumab (MEDI4736), an anti-PD-L1 human antibody, was well tolerated and associated with durable responses in pts with solid tumors. PD-L1 expression on myeloblasts is upregulated in MDS pts following HMA exposure. This randomized, open-label, phase II study evaluates the efficacy and safety of CC-486 ± durvalumab in pts unable to tolerate, or who fail to respond to, prior HMA therapy. Methods: This study consists of a run-in phase exploring the safety and tolerability of CC-486 ± durvalumab, followed by a randomized treatment phase (Table). Pts aged ≥ 18 years with FAB-defined MDS ( < 30% marrow blasts) who failed on prior HMA therapy are eligible. Primary endpoint is proportion of pts achieving an objective response (hematologic improvement, partial response, complete remission [CR], or marrow CR). Secondary endpoints include overall survival, time to/duration of response, progression-free survival, AML progression, and safety. Exploratory analyses include molecular biomarker assessments. Enrollment in the CC-486 arm began in July 2015. Target enrollment is 194 pts. Clinical trial information: NCT02281084.Safety run-in. Dose level, N ≥ 3 CC-486, twice daily Durvalumab Starting dose 200 mg 21/28d 1,500 mg i.v. 1/28d −1 150 mg 21/28d −2 100 mg 21/28d −3 100 mg 14/28d Randomized treatment (1:1) Allocation 2 phases Dose CC-486 SD ≥ 3 responders in 16 pts = additional 25 pts Based on safety run-in data ≤ 6 28d cycles PD CC-486 + durvalumab SD PD d, day; i.v., intravenous; PD, progressive disease; SD, stable disease.
How do they view us? Oncology providers’ perceptions of early/concurrent palliative care.
Authors: Dilip Sankar Babu, J Nicholas Dionne-Odom, Lisa Zubkoff, Tasha Smith, Marie Bakitas
Journal: Journal of Clinical Oncology (2015)

114 Background: Early integration of palliative care has been increasingly recognized as an important component in the care of cancer patients, including during active anticancer treatment. Yet, palliative and supportive care interventions remain to be well integrated into standard oncology practice. We sought to develop an original survey instrument in order to describe oncology providers’ perceptions of palliative care, particularly when introduced in the early and concurrent setting. Methods: We conducted a systematic review of literature pertaining to perceptions of palliative care and barriers to referral, and extracted survey items where they were found. This pool of questions was narrowed to focus on early/concurrent palliative care, and supplemented with original items. The draft survey was then systematically validated using a standardized scoring system and content-validity approach. Results: Twenty-two studies were reviewed. From an initial pool of fifty items, twenty-nine were selected for the draft survey. The draft was then reviewed by ten oncology providers, who scored each item and provided comments. Conclusions: We have produced a fully validated survey instrument that will be used to characterize oncology providers’ perceptions of early and concurrent palliative care interventions. The validated survey will be administered to oncology clinicians (including nurses, social workers and chaplains) at four academic medical centers at which an early palliative care intervention is currently being implemented. We hope to assess perceptions before and after implementation of the early palliative care intervention.
Abstract 875: Acquisition of chemoresistance in tumor cells requires crosstalk between dying and remnant live tumor cells via HMGB1
Authors: Junmin Zhou, Xianghong Chen, Danielle L. Gilvary, Melba Marie Tejera, Erika A. Eksioglu, Thu Le Trinh, Sheng Wei, Julie Djeu
Journal: Cancer Research (2016)

Abstract Chemoresistance often develops during drug treatment in cancer patients but its mechanism remains unclear. To understand acquisition of drug resistance, we investigated whether tumor cells dying during drug treatment might signal to neighboring live cells to program themselves for survival in the drug-containing environment. The experimental design was to identify a factor in the supernatants of docetaxel (DTX)-treated human DU145 and PC3 prostate tumor cells that could cause live tumor cells to resist apoptosis and cell death under docetaxel. We discovered that dying cells release HMGB1 which can bind TLR4 or RAGE on live tumor cells causing the induction of cytoplasmic Clusterin (CLU). We demonstrated that CLU is a potent prosurvival protein that can trap Bax from translocating to the mitochondria to cause caspade 3 activation and subsequent apoptosis. Proof of this pathway came from the ability of anti-HMGB1to prevent supernatants from dying cells to induce CLU in newly-plated tumor cells. The receptors for HMGB1 were identified by use of anti-TLR4 and anti-RAGE, which prevented recombinant HMGB1 or dying cell supernatants from inducing CLU in newly-plated tumor cells, causing them to subsequently succumb to DTX toxicity. Moreover, overexpression of anti-sense CLU in tumor cells abrogated their ability to respond to recombinant HMGB1 or dying cell supernatants to induce drug resistance. Most importantly, standard chemotherapeutic agents including gemcitabine, taxol, Ara-C, doxorubicin, cisplatin, etoposide and carboplatin, can cause the release of HMGB1 from dying tumor cells, implicating this crosstalk between dying and live tumor cells as a common pathway towards multi-drug resistance. Citation Format: Junmin Zhou, Xianghong Chen, Danielle L. Gilvary, Melba Marie Tejera, Erika A. Eksioglu, Thu Le Trinh, Sheng Wei, Julie Djeu. Acquisition of chemoresistance in tumor cells requires crosstalk between dying and remnant live tumor cells via HMGB1. [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 875.
Abstract 373: Discovery of selective PI3Kb inhibitors for PTEN-deficient tumors and other indications
Authors: Arnab R. Chowdhury, Jeyaraj D. Athisayamani, Sayan Mitra, Srinivas Maddi, Ram Sudheer Adluri, Sridhar R. Bethi, Hemant Joshi, Vijaya G. Tirunagaru, Jang B. Gupta
Journal: Cancer Research (2016)

Abstract PTEN somatic mutations occur in a large percentage of human cancers, from breast to prostate. Deletions of PTEN e.g. in prostate cancers are associated with tumor aggression and poor outcome, and up to 70 percent of prostate cancer patients have lost one copy of the PTEN gene at the time of diagnosis. Recent pharmacologic and genetic studies have identified the β isoform of PI3K to be required for growth of PTEN-deficient tumors in vivo and highly potent compounds are currently being explored in the clinic. These clinical candidates, however, are either limited by poor bioavailability or moderate selectivity against the delta isoform, thus warranting more selective compounds with better exposure. We have undertaken a comprehensive knowledge-based discovery of selective inhibitors of PI3Kβ with admissible pharmacokinetic and drug like properties. We have successfully identified a chemical series with potency ranging as low as 2.5 nM for PI3Kβ with &amp;gt;100 - fold selectivity for PI3Kδ. The α and γ isoform selectivity was around 1000 and 500 fold respectively. Compounds did not decrease insulin sensitivity and T cell proliferation thus mitigating the PI3Kα and PI3Kδ mediated side effects of nonselective inhibitors. In vitro biochemical potency translated into cell survival assay and pAKT target engagement in recombinant and wild type mammalian cell lines. In vivo tumor regression was observed in xenograft models of prostate cancer. The series did not show any observable hERG or CYP liabilities. The considerable potency, high selectivity and good bioavailability of this novel class of compounds not only makes them attractive for prostate cancer, but also for rare disease indications like hamartoma and other drug resistant cancers that are dependent on PTEN deletions. Citation Format: Arnab R. Chowdhury, Jeyaraj D. Athisayamani, Sayan Mitra, Srinivas Maddi, Ram Sudheer Adluri, Sridhar R. Bethi, Hemant Joshi, Vijaya G. Tirunagaru, Jang B. Gupta. Discovery of selective PI3Kb inhibitors for PTEN-deficient tumors and other indications. [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 373.
The Plasma Cell Transcription Factor XBP1 is Required To Mitigate The Unfolded Protein Response In Ph+ ALL
Authors: Behzad Kharabi Masouleh, Huimin Geng, Christian Hurtz, Chuanxin Huang, Lai N. Chan, Srividya Swaminathan, Haibo Sun, H. Phillip Koeffler, Ari Melnick, Elisabeth Paietta, Laurie H. Glimcher, Markus Muschen
Journal: Blood (2013)
Abstract 414: Biochemical and cellular monitoring of the activity of the ecto-5’-nucleotidase (CD73), a key cancer modulator using HTS-formatted bioluminescent technology
Authors: Said A. Goueli, Kevin hsiao.
Journal: Cancer Research (2016)

Abstract The ecto-5’-nucleotidase (CD73) is glycosylphosphatidylinositol (GPI) anchored cell surface protein that is involved in switching on adenosinergic signaling. Its enzymatic and nonenzymatic activities (via its interaction with extracellular matrix components) are involved in cancer associated processes and not completely independent of each other. It catalyzes the hydrolysis of AMP into adenosine and phosphate, where adenosine plays important role in tumor immune escape. It is overexpressed in many types of cancer cell lines and patient's biopsies including breast, colon, ovarian, gastric, ovarian, etc. In addition to being important as clinical and prognostic marker in cancer patients, overexpression of CD73 is associated with resistance to antitumor agents, and inhibition of CD73 activity or knocking it down by SiRNA reversed chemoresistant phenotype of glioblastoma multiforme cells. Because of the significant role of CD73, it is of importance to develop an assay that monitor the activity of CD73 in order to develop modulators of its activity. Towards this goal, we have developed a bioluminescent assay to monitor the activity of the enzyme in biochemically pure as well cellular anchored enzyme forms. The assay is homogenous and formatted for HTS screening research, very sensitive, and robust as indicated by the high Z’. We also show that the use of inhibitors such as adenosine 5’-(α-β-methylene) diphosphate (APCP) generates data with biochemically pure enzyme similar to the cellular bound form. We also demonstrate that cells that are enriched in CD73 can be easily identified from those that have low CD73. Thus, the current assay is robust, sensitive, and easy to use making it an ideal assay for HTS screening for new modulators of CD73 and generation of potential novel cancer therapeutics Citation Format: Said A. Goueli, Kevin hsiao. Biochemical and cellular monitoring of the activity of the ecto-5’-nucleotidase (CD73), a key cancer modulator using HTS-formatted bioluminescent technology. [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 414.
Abstract 3860: The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma
Authors: Cynthia M. Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Rena Shimizu, Maryam AbdusSumad, Hengbo Zhou, John Zapas, Valerie Calvert, Emaneul F. Petricoin, Michael B. Atkins, Stephen W. Byers, Dean S. Rosenthal
Journal: Cancer Research (2016)

Abstract Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that MBZ binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of dabrafenib-resistant BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation in vivo. RPPA and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were downregulated, consistent with S phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, an off-patent approved drug with no major side effects, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas. Citation Format: Cynthia M. Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Rena Shimizu, Maryam AbdusSumad, Hengbo Zhou, John Zapas, Valerie Calvert, Emaneul F. Petricoin, Michael B. Atkins, Stephen W. Byers, Dean S. Rosenthal. The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma. [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 3860.
PTH-247 Modern pelvic chemoradiotherapy techniques continue to cause bile acid malabsorption: Abstract PTH-247 Table 1
Authors: KL White, CC Henson, K Jenner, S Burden, S Lal, SE Davidson, J McLaughlin
Journal: Gut (2015)

<h3>Introduction</h3> During treatment with pelvic radiotherapy 80% of patients will develop diarrhoea. Patients with worse acute toxicity are at risk of developing more severe late bowel effects. It has previously been found that 44–57% of patients develop bile acid malabsorption (BAM) during pelvic radiotherapy. In the context of newer radiotherapy techniques, when there should be less small bowel exposure, we aimed to determine whether BAM remains a significant problem in this cohort of patients. <h3>Method</h3> This study was part of a trial evaluating the role of a gastrointestinal intervention for patients with cervical and bladder cancer receiving chemoradiotherapy. When patients developed lower gastrointestinal symptoms a SeHCAT scan was performed to detect BAM. Demographic and treatment data was recorded in the trial documentation. <h3>Results</h3> Twenty patients underwent a SeHCAT scan. Ten patients had cervical cancer and 10 had bladder cancer, of which 9 were male. All patients received 20 fractions of radiotherapy over 4 weeks. See table for full demographics. SeHCAT was completed a median 25 days following the start of radiotherapy (28 days for cervix group, 24 days for bladder group). Overall the prevalence of BAM was 65% (13/20). SeHCAT was positive in 90% of the cervix group and 40% of the bladder group. Of the 13 patients who had BAM the prevalence of mild (7-day retention 10–15%), moderate (7-day retention 5–10%) and severe BAM (7-day retention &lt;5%) were 23%, 31% and 46% respectively. There were no patients with 7-day retention of 15–20%. The median 7-day retention of all patients with BAM was 5% while for those without BAM it was 36%. Of the 4 patients who had VMAT (a newer technique), 3 had BAM suggesting that this technique is still strongly associated with small bowel effects. <h3>Conclusion</h3> Despite advances in radiotherapy techniques, we found a similar rate of BAM in this group compared to historical data. However the rate of BAM differed between the 2 patient groups suggesting that treatment factors may play a role and that these patient groups may not be homogeneous. <h3>Disclosure of interest</h3> K. White Grant/ Research Support from: This poster presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0211–10024. The views expressed are those of the author (s) and not necessarily those of the NHS, the NIHR or the Department of Health., C. Henson: None Declared, K. Jenner: None Declared, S. Burden: None Declared, S. Lal: None Declared, S. Davidson: None Declared, J. McLaughlin: None Declared.
Authors’ reply to Bosco-Lévy and Salvo
Authors: John A Romley, Cynthia Gong, Anupam B Jena, Dana P Goldman, Bradley Williams, Anne Peters
Journal: BMJ (2016)

We thank Bosco-Levy and Salvo for their comments,1 2 and we deal with each in turn.

Warfarin dosing is hard to measure in a claims database (because of important interaction with patient physiology), but glipizide/glimepiride dosing is more readily assessed. Bosco-Levy and Salvo are correct that hypoglycemia risk increases with dose. Our findings reflect low and high dose users, and future research should …