tbuckley/cabot-search huggingface dataset:
Abstract 3563: Ras-mediated regulation of cytochrome c-induced caspase activation is dependent on the status of extracellular matrix attachment
Authors: Chelsea M. McCallister, Raju Rayavarapu, Nicholas Pagani, Brendan Heiden, Melissa Shaw, Sydeny Shuff, Zachary T. Schafer
Journal: Cancer Research (2016)

Abstract Hyperactivating mutations in Ras are found in a significant percentage of cancers, with a particularly high frequency in pancreatic and colon carcinomas. The hyperactivation of Ras drives a vast number of distinct downstream signaling pathways that play an important role in disease progression. One outcome of overactive oncogenic Ras signaling is the inhibition of anoikis, a form of apoptotic cell death caused by detachment from the extracellular matrix (ECM). It is well-established that one mechanism of anoikis inhibition by Ras involves impaired mitochondrial cytochrome c release. In addition, here, we have found that Ras-mediated anoikis inhibition can also occur downstream of mitochondrial cytochrome c release. Our data suggest that anoikis inhibition following cytochrome c release is not dependent on changes in the abundance of the Apaf-1, pro-caspase-9, or pro-caspase-3. Instead, our data suggest that Ras signaling leads to an inhibition in the ability of caspase-9 to bind Apaf-1 which thereby inhibits proper formation of the apoptosome and caspase activation. Interestingly, in stark contrast to the inhibition of cytochrome c-induced apoptosis in ECM-detached cells, the overexpression of oncogenic Ras in ECM-attached cells results in enhanced sensitivity to exogenous cytochrome c. This sensitization was found to be due to upregulation of apoptosomal proteins (e.g. Apaf-1, pro-caspase-9) in an ERK/MAPK dependent manner. In aggregate, our data suggest that in addition to inhibiting the release of cytochrome c in both attachment and detachment, oncogenic Ras drives additional mechanisms that prevent apoptosome formation and caspase activation in detachment. Furthermore, our data support a model whereby ECM-attached cells containing oncogenic Ras mutations could be selectively eliminated by cytochrome c or agents that mimic its action. Citation Format: Chelsea M. McCallister, Raju Rayavarapu, Nicholas Pagani, Brendan Heiden, Melissa Shaw, Sydeny Shuff, Zachary T. Schafer. Ras-mediated regulation of cytochrome c-induced caspase activation is dependent on the status of extracellular matrix attachment. [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 3563.
Abstract 3224: Blocking FSTL1 reprograms cancer-caused abnormal immunity
Authors: Chie Kudo-Saito, Masayoshi Toyoura, Yuji Shoya, Akiko Ishida, Ryoko Kon
Journal: Cancer Research (2016)

Abstract Purposes: The close connection between imbalanced immunity and tumor progression has been increasingly recognized, and a number of inhibitors for blocking immune inhibitory checkpoints have been established to improve the anti-tumor immunity in cancer patients. However, clinical responses are limited to a part of the treated patients. We previously identified FSTL1, which is significantly secreted from Snail+ metastatic tumor cells, as a key effector molecule in the cancer-caused immune suppression and dysfunction. FSTL1 generates and expands pluripotent mesenchymal stem cells (MSCs), which are able to generate various immunoregulatory cells and functionally impaired CD8-low T cells, and also to induce de novo tumor dissemination into bone marrow. FSTL1 also directly confers higher invasiveness on tumor cells (EMT induction). To prevent the FSTL1-caused vicious circulation for tumor progression, we attempted to establish anti-FSTL1 blocking mAbs. Results: We generated chicken/mouse chimeric anti-FSTL1 mAbs, which specifically recognized human and mouse FSTL1. The anti-FSTL1 mAb significantly suppressed tumor proliferation and invasion, MSC induction in mouse bone marrow cells, and Treg induction in human PBMCs in vitro as compared to the control group. When bone metastatic melanoma models (C57BL/6 mice implanted with snail-transduced B16-F10 melanoma cells both subcutaneously and intravenously) were intraperitoneally injected with the anti-FSTL1 mAb (10 mg/kg) on Day 5 (when tumor metastasis was already observed in bone marrow) and Day 10 after tumor implantation, the FSTL1-caused events were inhibited, and tumor-specific CD8+ T cells with higher CTL activities were generated, resulting in significant suppression of subcutaneous tumor growth and bone metastasis in the treated mice as compared to those of the control mice. At least in the same models, conventional immune checkpoint inhibitors including anti-CTLA4, anti-PD1, and anti-PDL1 mAbs failed to improve the anti-tumor immunity, and rather promoted bone metastasis because of no reduction of regulatory cells, particularly the MSCs in the treated mice. Conclusions: These results suggest that blocking FSTL1 reprograms and properly induces anti-tumor immunity by switching the tumor-supportive immune directivity to the active mode against cancer. Our anti-FSTL1 mAb having totally different molecular mechanisms from the conventional ones may be a promising therapeutics as a next generation of “immune checkpoint inhibitors” for radically correcting cancer-manipulated immunity in clinical settings. Citation Format: Chie Kudo-Saito, Masayoshi Toyoura, Yuji Shoya, Akiko Ishida, Ryoko Kon. Blocking FSTL1 reprograms cancer-caused abnormal immunity. [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 3224.
Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial
Authors: Matthieu Allez, Brett E Skolnick, Maria Wisniewska-Jarosinska, Robert Petryka, Rune Viig Overgaard
Journal: Gut (2016)

<h3>Objective</h3> Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohn9s disease (CD). <h3>Design</h3> Seventy-eight patients (aged ≥18 and ≤75 years) with CD for ≥3 months, Crohn9s Disease Activity Index (CDAI) ≥220 and ≤450 and either C-reactive protein ≥10 mg/L or endoscopic evidence of inflammation, were randomised 1:1 to a single subcutaneous (SC) dose of 2 mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (ΔCDAI) from baseline to week 4. Prespecified significance level was 10% for CDAI endpoints. A futility analysis was instituted due to slow recruitment. <h3>Results</h3> Primary endpoint was not significantly different between anti-NKG2D and placebo (week 4 ΔCDAI=–16); however, there was a significant difference by week 12 (ΔCDAI=–55; p≤0.10). Significant improvements were noted in the non-failure to biologics subgroup (treated with anti-NKG2D (n=28)) from week 1 onward. Greater effects of anti-NKG2D were also observed in patients with baseline CDAI ≥330. Frequencies of adverse events (AEs) were comparable between anti-NKG2D and placebo. Most AEs were mild (49%) or moderate (43%). No antidrug antibodies were observed. <h3>Conclusions</h3> A single SC dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 versus placebo, but the difference was significant at week 12, and effects were evident in key subgroups. These data support further development of anti-NKG2D in IBD. <h3>Trial registration number</h3> NCT01203631.
Abstract 1805: CYP3A4 regulation of androgen receptor signaling in ER+ breast cancer
Authors: Priyatham Gorjala, Oscar Goodman Jr, Ranjana Mitra
Journal: Cancer Research (2016)

Abstract Purpose: Eighty percent of breast cancers that are estrogen receptor-positive (ER+) express AR. According to American Cancer Society, every two out of three women are ER+ and initially respond to estrogen-receptor targeted therapies but later almost 50% of breast cancers, despite the presence of ER, fail to respond. Acquired resistance to these therapies is common and portends a poor prognosis, frequently requiring the use of cytotoxic therapies. Our preliminary results indicate that endocrine-resistant tumors express higher levels of AR and may depend on AR for their growth. Hence AR targeted therapies may be appropriate for these resistant tumors. As we have recently demonstrated that CYP3A regulates androgen receptor signaling, we wish to ascertain the role of CYP3A in regulating AR in endocrine-resistant breast cancer. Methods: The ER+ cell lines MCF7 and T47D were used to study the role of AR in breast cancer. To study endocrine resistance in breast cancer, tamoxifen resistant MCF7 and T47D lines were generated with recurrent treatment of IC90 dosage of tamoxifen over 6 months’ time period. Cell fractionation, western blotting and q-RTPCR techniques were used to study the role of AR. siRNA inhibition of CYP3A4, the isoform expressed in breast, was used to study its role in regulating AR in breast cancer. Results: Our results indicate that both MCF7 and T47D express active AR, inducible by DHT and R1881. Similar to prostate cancer we also observe that AR in these lines is regulated by CYP3A4. Cell fractionation studies indicate that inhibition of CYP3A4 by siRNA results in reduced AR migration to the nucleus inhibiting its role as a transcription factor. Our results also indicate that tamoxifen resistant cell lines express increased levels of AR. Tamoxifen resistant cell lines respond to bicalutamide/enzalutamide with a lower IC50 value than the native cell lines, reflecting their AR dependence. The resistant cell lines also show increased AR nuclear migration with R1881 induction as compared to native breast cell lines. Conclusions: Endocrine-resistant breast cancer is sensitive to antiandrogen therapy. CYP3A4 may play an important role in endocrine-resistant breast cancer by negatively regulating AR activity. Citation Format: Priyatham Gorjala, Oscar Goodman Jr, Ranjana Mitra. CYP3A4 regulation of androgen receptor signaling in ER+ breast 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 1805.
Molecular Characterization Of a Patient With Thrombocytopenia-Absent Radii (TAR) Syndrome and Diffuse Langerhans Cell Histiocytosis (LCH): Novel Genetic Findings
Authors: Aakanksha Prasad Asija, Alina E. Dulau Florea, Xianguo Kong, Douglass A. Drelich, Srikanth Nagalla, Steven E. McKenzie
Journal: Blood (2013)
Abstract 21413: Feasibility of Adenosine Stress Dynamic CT for the Assessment of Myocardial Perfusion in a Porcine Animal Model
Authors: Florian Schwarz, Fabian Bamberg, Torleif Sandner, Elisabeth Baloch, Rabea Hinkel, Bernd Wintersperger, Maximilian Reiser, Konstantin Nikolaou
Journal: Circulation (2010)

Objective: To determine the accuracy of CT-based dynamic stress myocardial perfusion imaging to estimate myocardial blood flow (MBF) in a porcine animal model with variable degrees of coronary arte...
Serum collagen fragments and outcomes in hormone receptor-positive metastatic breast cancer.
Authors: Kim Leitzel, Suhail M. Ali, Monali K. Vasekar, Vinod Nagabhairu, Eric Marks, Ayesha Ali, Laura Krecko, Nicholas Willumsen, Diana Julie Leeming, Morten Asser Karsdal, Allan Lipton
Journal: Journal of Clinical Oncology (2016)

539 Background: 4 extracellular matrix (ECM) protein fingerprints in serum were correlated with outcomes in a phase 3 randomized clinical trial of 2nd-line hormone receptor-positive metastatic breast cancer: C1M (MMP-2/-9/-13 degradation of type I collagen), C3M (MMP-9 degradation of type III collagen), C4M (MMP-9/-12 degradation type IV collagen), and PRO-C3(true type III collagen formation). Methods: The pretreatment serum bank from 155 trial patients was evaluated using ELISA assays for the 4 ECM protein fingerprints and then correlated with TTP and OS. Results: In univariate analysis for TTP using the ECM fingerprints: 1) on a continuous basis, higher PROC3 was significant for shorter TTP, but C1M, C3M and C4M were not; 2) on a categorical basis (75th percentile), elevated C1M and C3M were significant for shorter TTP, but C4M and PROC3 were not. For overall survival (OS) using the ECM protein fingerprints: 1) on a continuous basis, higher C1M, C4M, and PROC3 were associated with shorter OS, but C3M was not; 2) for OS at the 75th percentile, all 4 ECM fingerprints were significant: elevated C1M (HR = 2.34, p < 0.0001), C3M (HR = 1.64, p = 0.03), C4M (HR = 1.75, p = 0.015), and PROC3 (HR = 1.95, p = 0.005) predicted for shorter OS. In multivariate analysis, including all 4 ECM fingerprints and the dominant site of metastasis [soft tissue only (ST), bone +/- ST, visceral +/- others], for TTP: 1) on a continuous basis, only higher PROC3 remained a significant covariate for shorter TTP; 2) at the 75th percentile cutpoint, only elevated C1M (HR = 1.65, p = 0.029) remained significant for shorter TTP. In multivariate analysis for OS: 1) on a continuous basis, only higher C1M and PROC3 remained significant for shorter OS; 2) at the 75th percentile, elevated C1M (HR = 3.71 , p < 0.0001), C4M (HR = 1.7, p = 0.057), and PROC3 (HR = 1.63, p = 0.053) remained significant for shorter OS. Conclusions: In a phase 3 randomized clinical trial of second-line hormone therapy in hormone receptor-positive metastatic breast cancer, elevated levels of these serum ECM protein fingerprints were associated with shorter TTP and overall survival. The presence of collagen fragments in serum deserves further study in larger breast cancer trials.
Antibiotic Treatment for Febrile Urinary Tract Infection
Authors: Lucila Marquez, Debra L. Palazzi
Journal: JAMA Pediatrics (2016)

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Abstract 3601: Evaluation and quantification of biomarkers of DNA damage in human plucked hair
Authors: Aude-Marine Bonavita, Liam Walker, Adam Boanas, Nicola Tonge, Gregory Tudor, Cath Booth, Ben Reed
Journal: Cancer Research (2016)

Abstract The hair follicle is a well vascularised structure that contains rapidly dividing epithelial cells. As a result it is a potentially useful surrogate biomarker for less accessible but highly similar tissues, such as rapidly proliferating tumours. We have developed an ex vivo culture method to validate target expression changes following exposure to DNA damage and/or potential therapeutics. Proof of concept studies performed ex vivo can then inform the design of clinical validation studies. Earlier work evaluated the response of targets such as pERK, pAKT and pSMAD2 to various kinase inhibitors, whilst recently we have used the model to measure the DNA damage response (DDR) following exposure to UV radiation (as a model damaging agent) and more clinically relevant chemotherapeutic agents. Human plucked hair was placed in maintenance media in the presence of known chemotherapeutic agents (such as Gemcitabine, DNA topoisomerase inhibitor I, Irinotecan and Paclitaxel) or exposed to 0.2-0.5J/cm2 UVB radiation. Hairs were then fixed at a range of time points post-exposure and longitudinal sections labelled for various markers including pChk1, gamma-H2AX, p53, Ki67 and thymine dimers (TDM1). Quantitative image analysis to measure the level of labelling was performed using an Aperio® ScanScope®. Following UVB exposure thymine dimer formation occurred immediately on the hair and was stronger on the side directly facing the source of radiation. It was followed rapidly by phosphorylation of Chk1 localised in the inner root sheath at first (10min to 1h after injury), then gamma-H2AX and p53 induction in the outer root sheath. Further studies are looking at DNA damage response in an UV dose dependent manner. Chemotherapeutic agents known for their different mechanism of actions were tested at two concentrations with various responses depending on their mechanism of action. For example, Gemcitabine, which is linked to DNA polymerase inhibition, strongly induced p53 after 24h but no gamma-H2AX activity was seen above background level. We have profiled the large panel of responses for each chemotherapeutic agent, over an acute time course. The ex vivo plucked hair follicle method is a rapid and convenient way of studying the DDR induced by exposure to various DNA damage agents. This model allows for screening of novel chemotherapeutic agents to test their efficacy in preventing or treating DNA damage. Citation Format: Aude-Marine Bonavita, Liam Walker, Adam Boanas, Nicola Tonge, Gregory Tudor, Cath Booth, Ben Reed. Evaluation and quantification of biomarkers of DNA damage in human plucked hair. [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 3601.
Acute toxicity data from POUT: A phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer.
Authors: Alison J. Birtle, Lauren Maynard, Mark Johnson, Roger Kockelbergh, Rebecca Lewis, Michelle Newton, Robert J. Jones, John David Chester, Anthony Blacker, James Catto, Emma Hall
Journal: Journal of Clinical Oncology (2016)

e16138 Background: The POUT trial compares surveillance (surv) with immediate chemotherapy (CT), following nephroureterectomy (NU) (CRUK/11/027). The primary endpoint is disease free survival. Secondary endpoints include acute toxicity. Methods: Recruitment commenced 31/05/2012 and is ongoing. Patients (pts) with pT2-T4 pN0-3/pT1 pN+ M0 UTUC are randomized (1:1) following NU to surv with later CT if required or 4 cycles of gemcitabine with cisplatin or carboplatin (if GFR 30-49ml/min). Safety assessments (CTCAEv4) are conducted pre-randomization, pre-cycle 1,2,3,4, & after cycle 4 (equivalent timepoints for surv pts). Results: Acute toxicity data are available for an initial cohort of 129 pts: median age: 68.9 (IQR 62.4, 75.0); stage: 28.7% pT2, 65.1% pT3, 6.2% pT4; Nodal stage: 93.8% N0, 2.3% N1, 3.9% N2; baseline WHO performance status 57.4% 0, 34.9% 1, 0.8% 2, 7.0% missing; baseline median (IQR) GFR: 55 (44, 67). Gem-cis was planned for 64.3% pts (median (IQR) GFR: 64 (55, 72)), gem-carb for 35.7% (median (IQR) GFR: 43 (39, 46)). 46.8% (29/62) CT & 22.4% (15/67) surv pts had ≥ 1 grade 3-4 acute toxicity (p = 0.005). Grade 3-4 hematological (hem) toxicity occurred in 29.0% (18/62) CT pts & 0% (0/67) surv pts, with a peak at pre-cycle 2. Commonest hem toxicities were neutropenia (22.6% CT; 0% surv) & low platelet count (9.7% CT, 0% surv); febrile neutropenia was reported by 3.2% CT & 0% surv pts. Commonest grade 3-4 non-hem toxicity was hypertension (1.6% CT, 6.0% surv). Conclusions: Whilst toxicity rates are higher with CT than surv, they are lower than anticipated in this population. Clinical trial information: 98387754.Acute toxicities. CTCAE Grade Surv N = 67 CT N = 62 N % N % Worst grade on-treat toxicity 0 24 36 4 6 1-2 30 45 35 56 3-4 7 10 20 32 Missing 6 9 3 5 Worst grade on-treat hem toxicity* 0 53 79 13 21 1-2 7 10 27 44 3-4 0 0 18 29 Missing 7 10 4 6 Worst grade on-treat non-hem toxicity 0 26 39 7 11 1-2 27 40 46 74 3-4 7 10 6 10 Missing 7 10 3 5 *Hem toxicities are febrile neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase, decreased neutrophil count, and decreased platelet count
Drug monitoring of ERY001 (erythrocyte encapsulated L-asparaginase) and native L-asparaginase (L-ASP) in combination with COOPRALL regimen in Phase 3 randomized trial in patients with relapsed acute lymphoblastic leukemia.
Authors: Yves Bertrand, Andre Baruchel, Xavier G. Thomas, Nicolas Blin, Emmanuelle Tavernier Tardy, Yves Perel, Norbert Vey, Virginie Gandemer, Victoria Cacheux, Francoise Mazingue, Emmanuel Raffoux, Genevieve Plat, Maryline Poiree, Jean-Louis Stephan, Anne Auvrignon, Dominique Plantaz, Isabelle Pellier, Cecile Bonin, Iman El-Hariry, Alina Ferster
Journal: Journal of Clinical Oncology (2015)

e18036 Background: Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies (A-Abs), which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). ERY001 improves pharmacokinetics, tolerability and maintain circulating asparaginase (ASPA) activity due to the protective barrier of the erythrocyte membrane. This study assessed the activity of ASAP, formation of A-Abs and glutamine levels. Methods: This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the duration of ASPA activity > 100IU/L and the incidence of ASPA hypersensitivity during induction. The study was powered to detect 3-fold difference in the incidence of allergic reactions between treatments. Pts (n = 80), aged 1-55 years were randomized to ERY001 (150 IU/kg, n = 26 or L-ASP (10,000 IU/m², n = 28), or to ERY001-exp (prior allergy, n = 26). Results: At baseline, 58% of pts with prior allergy, and 23% and 28% of pts without prior allergy had +ve A-Abs, in ERY001 and L-ASP arms respectively. In the non-allergic pts, ERY001 significantly reduced the incidence of ASPA hypersensitivity (0% vs 43%; p < 0.001). ASPA activity > 100 IU/l was 21 ±5 vs 9± 8 days in ERY001 and L-ASP, respectively (p < 0.001), and 19 ± 6 days in ERY001-exp. ASPA activity was also longer in patients with silent activation (14± 5 vs 6± 4 days, ERY001 and L-ASP respectively). Glutamine levels were similar across treatment arms. Mean levels of glutamic acid were lower in standard risk pts treated with ERY001 (40± 20 umol/L), ERY001-exp (74± 82 umol/L) vs L-ASP (103 ± 78 umol/L), but similar cross treatment arms in high-risk pts. Asparagine depletion was also measured. Conclusions: These highly encouraging results show that ERY001 is a suitable option for patients with relapsed ALL maintaining ASPA efficacy with improved tolerability. Measuring asparaginase levels is recommended as a more accurate way of drug monitoring. Clinical trial information: NCT01518517.