tbuckley/cabot-search huggingface dataset:
Abstract 5199: A novel role for BAP1 in development and tumor suppression
Authors: Dawn A. Owens, Jeffim N. Kuznetsov, Stefan Kurtenbach, Tristan Agüero, Mary Lou King, J. William Harbour
Journal: Cancer Research (2019)

Abstract Uveal melanoma (UM) is the second most common form of melanoma and one of the most deadly types of cancer. Recent discoveries in our laboratory and others have led to a deeper understanding of the driver mutations UM. The initiating mutation that is present in virtually all UM occurs in one of four genes in the Gaq signaling pathway (the “Gaq” mutations) and result in sustained activation of proliferative signals. A second mutation occurs later in one of three genes – BAP1, SF3B1 or EIF1AX (the “BSE” mutations), which determines metastatic risk – BAP1 (high risk), SF3B1 (intermediate risk) or EIF1AX (low risk). Surprisingly, we recently discovered that the Gaq mutation and the subsequent BSE mutation occur very close in molecular time. This work suggests that Gaq mutations may cause epigenetic changes that predispose to BSE mutations. We have shown that BAP1-mutant UMs exhibit a de-differentiation and stem-cell like phenotype, suggesting that BAP1 may normally regulate differentiation programs during embryonic development. Consistent with this possibility, BAP1 loss in mouse is embryonic lethal. To study the role of BAP1 in early vertebrate development, therefore, we chose Xenopus laevis (African clawed frog), a widely used model for studying gene function during development. We found that targeted depletion of the Xenopus BAP1 protein (xBap1) causes a striking developmental phenotype affecting multiple germ layers, and that this phenotype is associated with disruption of super enhancers around differentiation genes that are normally maintained by BAP1. Taken together, these studies suggest that loss of BAP1 promotes tumor progression and metastasis, at least in part, by disrupting tightly controlled differentiation programs that govern cell identity. These findings may nominate new therapeutic targets in BAP1-mutant cancers. Citation Format: Dawn A. Owens, Jeffim N. Kuznetsov, Stefan Kurtenbach, Tristan Agüero, Mary Lou King, J. William Harbour. A novel role for BAP1 in development and tumor suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5199.
Abstract 983: Antibody-drug conjugates of NAMPT inhibitors: Discovery, optimization, and preclinical characterization
Authors: Chris Neumann, Kathleen C. Olivas, Kung Pern Wang, Andrew B. Waight, David W. Meyer, Luke V. Loftus, Margo C. Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman, Fu Li, Michelle L. Ulrich, Abbie Wong, Weiping Zeng, Robert P. Lyon, Peter D. Senter
Journal: Cancer Research (2019)

Abstract Nicotinamide phosphoribosyltransferase (NAMPT) regulates the biosynthesis of NAD from nicotinamide via a salvage biosynthetic pathway. Inhibition of NAMPT depletes cellular NAD levels leading to disruption of energy metabolism and cell death. Non-targeted small molecule NAMPT inhibitors have demonstrated poor tolerability in clinical trials and in preclinical models, including cardiac and retinal toxicities in rats. In an effort to improve the therapeutic window of this drug class, we pursued a targeted-delivery approach using antibody-drug conjugates. Through a medicinal chemistry effort, we identified novel NAMPT inhibitors that incorporate chemical functionality in the solvent-exposed terminus to allow construction of enzyme-cleavable drug linkers. Additionally, we applied a pyridinium-based linker strategy that allows for traceless linker attachment through a conserved nicotinamide-mimetic moiety of NAMPT inhibitors. Candidate molecules were evaluated for NAMPT binding affinity and cellular cytotoxicity as free drugs, and for cellular cytotoxicity as ADCs with the alternate linker strategies. Comparisons across inhibitors and linker strategies provide insight into optimal design of cleavable drug linkers for this class of drugs. In vitro, the ADCs deplete NAD and lead to downstream ATP depletion in a time-dependent manner. In vivo evaluation using human tumor xenografts shows translation of the pharmacodynamic effect resulting in tumor regression in models of Hodgkin lymphoma, non-Hodgkin lymphoma, and acute myeloid leukemia. Toxicology studies in Sprague Dawley rats demonstrate excellent tolerability at active doses, with no observable cardiac or retinal toxicities at the highest tested doses in single- and multi-dose regimens. These findings detail the development of a novel payload class and optimized linker strategy for use with antibody-drug conjugates, and demonstrate a preclinical efficacy and safety profile to support continued efforts toward clinical therapeutics. Citation Format: Chris Neumann, Kathleen C. Olivas, Kung Pern Wang, Andrew B. Waight, David W. Meyer, Luke V. Loftus, Margo C. Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman, Fu Li, Michelle L. Ulrich, Abbie Wong, Weiping Zeng, Robert P. Lyon, Peter D. Senter. Antibody-drug conjugates of NAMPT inhibitors: Discovery, optimization, and preclinical characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 983.
Markers of Collagen Formation and Degradation Reflect Renal Function and Predict Adverse Outcomes in Patients With Type 1 Diabetes
Authors: Sascha Pilemann-Lyberg, Daniel Guldager Kring Rasmussen, Tine Willum Hansen, Nete Tofte, Signe Abitz Winther, Signe Holm Nielsen, Simone Theilade, Morten Asser Karsdal, Federica Genovese, Peter Rossing
Journal: Diabetes Care (2019)

OBJECTIVE Patients with type 1 diabetes (T1D) have a higher risk of developing chronic kidney disease, cardiovascular events (CVEs), and mortality than the general population. We hypothesized that two previously published biomarkers, namely PRO-C6, a biomarker of collagen type VI formation, and C3M, a biomarker of collagen type III degradation, may be associated with impaired renal function and have prognostic value for adverse renal, CVE, and mortality in patients with T1D. RESEARCH DESIGN AND METHODS PRO-C6 and C3M in serum (sPRO-C6, sC3M) and urine (uPRO-C6, uC3M) were measured by ELISA in 663 patients with T1D ranging from normoalbuminuric to macroalbuminuric. Association of the biomarkers with mortality, CVEs, heart failure, decline in estimated glomerular filtration rate (eGFR) ≥30%, and end-stage renal disease (ESRD) were tested in Cox proportional hazards models after log2 transformation and adjusted for relevant clinical characteristics. Hazard ratios (HRs) were reported per doubling of biomarker levels. RESULTS High levels of sPRO-C6 were independently associated with a higher risk of all-cause mortality (HR 2.26 [95% CI 1.31–3.87], P &amp;lt; 0.0031). There was an association with higher risk of CVEs (n = 94) and heart failure (n = 28) but not after adjustment (P ≥ 0.58). In relation to renal outcomes, adjusted sPRO-C6 was associated with a higher risk of eGFR decline ≥30% in T1D, with eGFR &amp;gt;45 and &amp;gt;30 mL/min/1.73 m2, and with a higher risk of ESRD (all P ≤ 0.03). Higher uPRO-C6 was associated with a lower risk of decline in eGFR. CONCLUSIONS In patients with T1D, higher sPRO-C6 was an independent predictor of both decline in eGFR and development of ESRD and of all-cause mortality. Higher uPRO-C6 was also associated with a lower risk of decline in eGFR.
Abstract P255: Body Mass index, C-Reactive Protein and Mortality among Coronary Artery Disease Patients
Authors: Ding Ding, Min Wang, Dongfang Su, Changjiang Hong, Xinrui Li, Yuan Zhang, Gang Hu, Wenhua Ling
Journal: Circulation (2015)

Background:  The association between BMI and mortality is debated among coronary artery disease (CAD) patients. C-reactive protein (CRP), a harmful predictor for CAD, may be linked with the above association.   Objectives:  The present study was to investigate the single and joint associations of BMI and CRP with mortality.   Methods:  The study included 1980 Chinese CAD patients who were 40-85 years of age in the Guangdong Coronary Artery Disease Cohort. Cox proportional hazards regression models were used to estimate the association of BMI and serum CRP with death risk.   Results:  During a median follow-up of 3.1 years, 141 deaths were recorded, 110 were due to cardiovascular disease (CVD). After adjustment of major CVD risk factors, there was a J-shaped association between BMI and all-cause and CVD mortality, and a positive association between CRP and mortality. The J-shaped association of BMI with mortality was present among patients with elevated CRP (≥3.0 mg/L). Compared with overweight (BMI 24-27.9 kg/m 2 ) patients with normal CRP concentration ( 2 ) with elevated CRP concentration had a 3.41-fold risk of all-cause mortality (95% CI 1.49-7.80) and a 3.50-fold risk of CVD mortality (1.40-8.75), lean patients (BMI 2 ) with elevated CRP concentration had a 2.54-fold risk of all-cause mortality (1.36-4.74) and a 2.36-fold risk of CVD mortality (1.19-4.70). When we did an additional analysis among patients who never smoked, the J-shaped association of BMI with all-cause and CVD mortality was confirmed among non-smokers. When we excluded the participants who died during the first year of follow-up (n= 61), the J-shaped association did not change.   Conclusions:  The present study found a J-shaped association of BMI with all-cause and CVD mortality, and a positive association between serum CRP and all-cause and CVD mortality 2 among Chinese CAD patients. This J-shaped association was only observed among patients with elevated CRP concentration. For patients with normal CRP concentration, the risk of death increased with BMI levels.
Increasing severity of atopic dermatitis is associated with a negative impact on work productivity among adults with atopic dermatitis in France, Germany, the U.K. and the U.S.A.
Authors: L. Andersen, M.E. Nyeland, F. Nyberg
Journal: British Journal of Dermatology (2019)

Atopic dermatitis (AD) is associated with high disease burden, with a significant physical and social impact. However, the association between disease severity and burden of disease, with work productivity and daily activities being one aspect, has not been well characterized. To investigate the impact of disease severity on work productivity and daily activities among adults with AD in Europe (France, Germany and the U.K.) and the U.S.A. The survey panel participants for this cross‐sectional internet‐based survey on AD were sourced from the population‐based National Health and Wellness Survey (Europe 2016, U.S.A. 2015 and 2016). AD severity was determined by Patient‐Oriented Scoring Atopic Dermatitis (PO‐SCORAD). Work productivity and work activity impairment were assessed using the Work Productivity and Activity Impairment (WPAI) – Specific Health Problem questionnaire for AD. The study survey was completed by 1098 respondents with moderate‐to‐severe AD and 134 with mild AD. Overall, the negative impact on work productivity (all WPAI items) was suggested to increase with increasing AD severity (PO‐SCORAD) at the regional level (Europe and U.S.A.) and in the total sample. For overall work impairment due to AD, respondents with mild AD reported a mean of 2·4 h per week of potential work productivity lost, respondents with moderate AD 9·6 h and respondents with severe AD 19·0 h. Higher AD severity was associated with a greater negative impact on work productivity in adults. This impact is a burden not only for the patient but also for society and may provide incentives for treatment optimization and more effective management of AD. What's already known about this topic? Atopic dermatitis (AD) is associated with a high disease burden. AD has a negative impact on several aspects of health‐related quality of life, one of which is work productivity. What does this study add? By using a population of participants with AD recruited from the National Health and Wellness Survey, which collects broad and representative data from the general population, survey data could be obtained from U.S. and European populations of patients with AD. The present study suggests an increasingly negative impact on work productivity with increasing severity of AD. The data indicate no regional differences in the impact of AD severity on work productivity.
Lisocabtagene maraleucel (liso-cel) treatment of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) and secondary CNS lymphoma: Initial results from TRANSCEND NHL 001.
Authors: Jeremy S. Abramson, Maria Lia Palomba, Jon E. Arnason, Matthew Alexander Lunning, Scott R. Solomon, Thalia Farazi, Jacob Garcia, Benhuai Xie, Kathryn J. Newhall, Christine Dehner, Tanya Siddiqi
Journal: Journal of Clinical Oncology (2019)

7515 Background: No clinical studies have yet evaluated CAR T cell therapies in pts with R/R B-cell NHL who have secondary CNS lymphoma. We report data from this pt subgroup receiving liso-cel (JCAR017), an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the phase 1 TRANSCEND NHL 001 study. Methods: Eligible pts had confirmed B-cell NHL with R/R disease after ≥2 prior lines of therapy. Pts with secondary CNS lymphoma could enroll or, if it developed on study, could continue to receive liso-cel. After lymphodepleting chemotherapy, liso-cel was administered at 1 of 2 dose levels (DL): DL1 = 50 × 10 6 or DL2 = 100 × 10 6 total CAR+ T cells. Efficacy was evaluated per the Lugano criteria. Pts achieving a complete response could be retreated with liso-cel upon progressive disease. Results: At data cutoff, 9 pts with secondary CNS lymphoma at initial treatment (n = 6), retreatment (n = 2), or cycle 2 (n = 1) received liso-cel. 4 pts were treated at DL1 and 5 at DL2. The median (range) age was 60 (47‒73) years and number of prior lines of therapy was 3 (2‒7). Median time to peak CAR+ T cell expansion was 12.5 (7–112) days. 1 of 9 pts had grade (G)2 cytokine release syndrome (CRS) and 1 of 9 pts had a neurological event (NE; G3 decreased level of consciousness). No retreatment pts had CRS or NE; however, 1 retreatment pt had an NE of G2 temporal edema with initial treatment with liso-cel. 5 pts received prophylactic levetiracetam. 1 pt received corticosteroids and tocilizumab. Other toxicities were predominantly cytopenias. There were no treatment-related deaths. 4 pts responded to liso-cel; all had a best response of complete response, of which 2 are ongoing at 270 and 545 days post-liso-cel. All 4 responses occurred after initial liso-cel treatment; no retreated pts responded. Conclusions: In the ongoing TRANSCEND NHL 001 study, liso-cel continues to demonstrate the ability to be safely delivered to pts with R/R B-cell NHL, including those with secondary CNS lymphoma, a population of pts with a highly unmet medical need. No excess NE was noted in this population. This cohort continues to be evaluated. Clinical trial information: NCT02631044.
Abstract 86: Pentraxin 3 Can Be A Candidate For Biomarker Of Kawasaki Disease
Authors: Yasuhiro Katsube, Miharu Akao, Yoshiaki Hashimoto, Kouji Hashimoto, Makoto Watanabe, Masanori Abe, Ei Ikegami, Mitsuhiro Kamisago, Ryuji Fukazawa, Shunichi Ogawa
Journal: Circulation (2015)

Background: Kawasaki disease (KD) is a systemic vasculitis and the leading cause of acquired heart disease. There are some cases that show unresponsiveness to initial intravenous immunoglobulin (IVIG) and require addition treatment. High incidence of coronary artery lesions (CAL) is seen in unresponsive cases. Pentraxin 3 (PTX3) is produced at the site of vascular inflammation, and used as a new biomarker for vasculitis. The aim of this study is to explore the application of PTX3 to KD. Methods: 128 patients with KD are enrolled. Blood samples are collected at before IVIG and 1, 3, 6 month later from the onset of KD. PTX3 values are compared with IVIG unresponsive scoring system by Kobayashi et al. (Circulation, 2006). Results: Mean values of PTX3 before IVIG and 1, 3, 6 month were respectively 25.1*, 7.1*, 3.8, 3.6 ng/ml (asterisk shows statistical significance with age-matched control: 3.6). Mean values of PTX3 in unresponsiveness (n=20) and responsiveness (n=108) at before IVIG and 1, 3, 6 month were 46.8* vs. 20.9, 9.1* vs. 6.7, 4.2 vs. 3.7, 3.9 vs. 3.5 ng/ml (asterisk shows statistical significance between two groups). There is statistical positive correlation between PTX3 and score points by Kobayashi et al. (r=0.602, p=0.000). According to the statistical analysis, the area under the ROC curve (AUC) was 0.87 and sensitivity and specificity of PTX3 as IVIG unresponsiveness prediction were 90 and 81 %, if cut off value was set as 28 ng/ml. Conclusions: 1. vasculitis continues at least 1 month after onset of disease. 2. PTX3 can be a candidate biomarker for prediction of unresponsiveness in patients with KD.
Abstract 4266: Endoplasmic reticulum (ER), a potential therapeutic target for mutant p53 colorectal cancer
Authors: Ashish Tyagi, Balaji chandrasekaran, Venkatesh Kolluru, Becca V. Baby, Alatassi Houda, Srinivasa Ramisetti, Arun Sharma, Murali Ankem, Chendil Damodaran
Journal: Cancer Research (2019)

Abstract Introduction: Inactivating p53 mutations contribute to tumor progression and treatment-resistance, resulting in poor patient survival in colorectal cancer patients (CRC). The goal of this study is to identify novel small molecules that therapeutically target mutant p53 in CRC. Methods: We analyzed the effects of small molecule (ASR458) on p53-wild type (p53-wt; HCT116) and mutant p53 (p53-mut; SW620) colon cancer cells by phenotypic, molecular and in vivo assays. Results: ASR458 treatment significantly inhibited the proliferation of both HCT116 and SW620 cells at nM concentrations. In p53-wt HCT116 cells, ASR458 caused induction of p53 that resulted in caspase-mediated cell death in both in vitro and in vivo models. On the contrary, ASR458 treatment induced ER-stress signaling (i.e., phosphorylation of ERK and eIF2-α) in p53-mut SW620 cells, which triggered ATF4 activation and subsequent induction of cascade of autophagy events (Atg family proteins, LC3B and Lamp1), causing autophagy-mediated cell death. Silencing ER stress marker ATF-4, a key regulator of autophagy, caused resistance to ASR458 and abrogated autophagy signaling in SW620 cells. This suggested that induction of ER-stress is critical for the cytotoxic effects of ASR458 in p53-mut CRC. Preliminary knockdown studies indicate that silencing of ER markers causes resistance to ASR458 in vitro, further confirming ER-stress as the mechanism of ASR458 action in p53-mut CRC. ASR458 significantly inhibited the growth of SW620 tumors in xenograft. Tissue analysis confirmed the ER-stress signaling observed in vitro. Conclusion: Our results demonstrate ASR458 as a potential therapeutic agent with distinct targets in p53-wt and p53-mut CRC. This study also suggests that ATF4 mediated autophagy in unmanaged ER stress can reduce CRC pathogenesis. Further investigation into the pharmacokinetics and pharmacodynamics of ASR458 should help clinical translation of this agent. Citation Format: Ashish Tyagi, Balaji chandrasekaran, Venkatesh Kolluru, Becca V. Baby, Alatassi Houda, Srinivasa Ramisetti, Arun Sharma, Murali Ankem, Chendil Damodaran. Endoplasmic reticulum (ER), a potential therapeutic target for mutant p53 colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4266.
Abstract O.68: Corticosteroid Pulse Therapy for Acute Kawasaki Disease: Consideration for the Long-Term Prognosis of Coronary Artery Lesions
Authors: Atsushi Kitagawa, Masahiro Ishii, Yoshihito Ogihara, Shouhei Ogata, Motofumi Iemura, Kenji Suda
Journal: Circulation (2015)

Background: The use of corticosteroids as treatment for Kawasaki disease (KD) patients is still controversial. And the effects of corticosteroids on coronary artery lesions (CALs) development and later vascular remodeling are also unclear. The purpose of this study was to compare the long term prognosis of KD with CALs between corticosteroid administration patients and no corticosteroid using patients. Methods: Five hundred sixty nine patients with KD were studied at Kurume University Hospital from 1996 to 2004. Clinical records of 66 patients (46 males, 20 females) with CALs were reviewed. The median age at diagnosis was 1.5 (range 0.2 - 13.2) years and median follow-up period was 8.9 (range 0.1 - 16.4) years. Coronary artery sizes were measured by body surface area (BSA) adjusted z-score to using echocardiography. CALs were defined as coronary artery z-score &gt; 2.5, and CAL regressions were defined as z-score &lt; 2.5. Results: Sixty four patients were treated with intravenous immunoglobulin (IVIG), and 51 (79.7%) patients were unresponsive to the initial IVIG treatment. Twenty seven (40.9%) patients were received corticosteroid pulse therapy in the acute phase. The maximum CAL z-score in the acute phase, there were not significant differences between corticosteroid administration patients and no corticosteroid using patients (5.1 ± 2.2 vs. 4.9 ± 2.3, p = 0.277). The CAL z-score at the end of this study period, there were not significant differences between two groups (2.1 ± 2.0 vs. 2.3 ± 2.3, p = 0.432). The ratio of CAL regression in the study period (33.3% vs. 46.2%), the mean interval between the onset of KD and CAA regression (0.6 ± 0.5 vs. 0.8 ± 0.5 years, p = 0.209), and the ratio of coronary artery stenosis or occlusion (14.8% vs. 15.4%), there were not significant differences between two groups. Conclusion: Corticosteroid pulse therapy for KD patients may not be worsened CALs in the acute phase and long-term after the onset.
Abstract 2301: Antiglycan antibodies as predictors of therapeutic outcome in cervical cancer patients
Authors: SHARAD PUROHIT, Paul M. Tran, Lynn K. Tran, Xuezheng Song, Ferris G. Ferris, John J. Wallbillich, Boying Dun, Jin-Xiong She
Journal: Cancer Research (2019)

Abstract Cervical cancer is a significant cause of cancer related death among women, with the highest mortality rates in developing countries. We aim to identify serum biomarkers for predicting outcome of radio therapy alone or combination of radiotherapy and brachytherapy. We measured natural anti-glycan IgG antibodies in the serum of stage II (n=276) and III (n=292) cervical cancer patients treated with radiation alone or in combination with brachytherapy on a suspension glycan array containing 184 glycans. Overall and progression free survival was used to determine the treatment outcome by Kaplan-Meier and Cox proportional hazards ratio. Significant protective effects were observed for Blood Group H antigens (HR=0.642, p=0.0013), Lewis Antigens (0.72, 0.015; 0.654, 0.003), Galili antigens (0.671, p=0.004), and other glycans belonging to Isoglobo (0.671,0.004) and 3fucosyllactose series (0.687,0.004). The protective effects remained significant after adjusting for stage and treatment. Our data suggest that measurement of natural anti-glycan IgG antibodies in serum can predict outcome of therapy in cervical cancer patients. Citation Format: SHARAD PUROHIT, Paul M. Tran, Lynn K. Tran, Xuezheng Song, Ferris G. Ferris, John J. Wallbillich, Boying Dun, Jin-Xiong She. Antiglycan antibodies as predictors of therapeutic outcome in cervical cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2301.