tbuckley/cabot-search huggingface dataset:
Abstract 15427: Oxidative Stress From Altered Cardiac β3-adrenergic Receptor-activated Inducible Nitric Oxide Synthase/NO Pathways Promotes Cardiac Aging
Authors: Che Ping Cheng, Heng-Jie Cheng, Peng Zhou, Tiankai Li, Xiaowei Zhang, Dalane Kitzman, Michael Callahan
Journal: Circulation (2015)

Background: There is substantial evidence supporting oxidative stress as an important mechanism to age-related cardiac dysfunction and altered β 3 -adrenergic receptor (AR)-activated nitric oxide synthase (NOS) pathway contributing to this process. However, the NOS isoforms involved are controversial. The mechanism of how β 3 -AR stimulation impacts ROS, SERCA2a, and cardiac function in cardiac aging (CA) is unclear. We tested the hypothesis that oxidative stress from up-regulation of cardiac β 3 -AR-activated iNOS uncoupling promotes CA. Methods: We compared myocyte subtypes of β-ARs, three NOS, peroxynitrite (NT), NADPH, GTPCH and SERCA2a expressions and myocyte contractile and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses to β-AR stimulation with isoproterenol (ISO, 10 -8 M). LV myocytes were isolated from 2 young (Y) (~4 to 6 m) and 2 aged (A) (~28 to 31 m) groups (5/group) of wild-type (WT) and β 3 -AR knockout (β 3 KO) mice. Results: Compared to YWT, AWT myocytes had significantly increased protein levels of β 3 -AR (0.31 vs 0.16) and iNOS (0.48 vs 0.21) accompanied with increased oxidative stress indicated by significant increases in NT formation (increased 102%) and NADPH (P67 -phox , 35% and p22 -phox , 28%), but decreased GTPCH expression (41%, 0.48 vs 0.82) and activity. AWT myocytes had significantly decreased β 1 -AR protein (0.38 vs 0.59), SERCA2a (0.26 vs 0.72) and the ratios of SERCA2a/PLB. These changes were associated with reduced basal cell contraction (dL/dt max, 76.4 vs 122.8 μm/s), relaxation (dR/dt max , 58.9 vs 94.3 μm/s), and [Ca 2+ ] iT (0.16 vs 0.24) accompanied by diminished β-AR-stimulated positive inotropic response. Importantly, in contrast to age-caused changes in AWT, versus Yβ 3 KO, in Aβ 3 KO myocytes, there were no significant alterations in iNOS (0.19 vs 0.16), NT (increased 9%), β 1 -AR (0.60 vs 0.62), and SERCA2a (1.2 vs 1.4). Aβ 3 KO myocytes had normal cell contraction and relaxation with preserved ISO-stimulated positive inotropic response. Conclusions: Myocardial aging is associated with up-regulation of cardiac β 3 -AR-activated iNOS pathway, which leads to imbalance in NO/superoxide production, favoring subsequent iNOS uncoupling and directly contributes to age-associated deficits in LV myocyte function and [Ca 2+ ] i regulation.
Idiopathic Pulmonary Fibrosis
Authors: Hedi Orbach, Maria Karlinskaya, Oren Fruchter
Journal: New England Journal of Medicine (2018)

Idiopathic pulmonary fibrosis is a severe disorder mainly affecting lungs. It occurs more frequently in smokers or former smokers with an average age of onset around 65. The first pathogenetic event leading to the complete derangement of lung parenchyma is the alveolar stem cell exhaustion due to intrinsic factors (genetic mutations or polymorphisms) and extrinsic insults (cigarette smoke, pollution). The histopathologic background is Usual Interstitial Pneumonitis. Transbronchial cryobiopsy allows harvesting of lung samples large enough to identify the characteristic of this morphologic pattern. The best strategy to maintain a high diagnostic yield is to biopsy at least two different segments.
Abstract 4888: Nuclear localization of antizyme inhibitor may be a marker for aggressiveness of prostate cancer
Authors: Aram Ghalali, James M. Rice, Liangzhe Wang, Chin Lee Wu, Michael S. Rogers, Bruce Zetter
Journal: Cancer Research (2019)

Abstract Antizyme suppresses cell cycle by inhibiting the polyamine synthesis through binding to the rate limiting enzyme ornithine decarboxylases (ODC). High levels of ODC have been reported in several forms of cancer, among them prostate cancer. Antizyme Inhibitor (AZIN) binds to antizyme and thereby blocks its inhibitory effect on ODC. Here, we have measured the expression and localization of AZIN in 202 prostate cancer specimens, along with 26 adjacent benign samples and found that nuclear localization of AZIN is associated with significantly lower survival. Upregulation and nuclear localization of AZIN have been observed in several cancers, as has editing of the AZIN1 mRNA. Others have hypothesized that the RNA- edited AZIN (edAZIN) may have an increased affinity to antizyme and that could explain the association of edAZIN to the various cancers. We have studied the mechanism behind the nuclear localization of AZIN and found the single base pair substitution caused by RNA editing is sufficient to result in nuclear localization of the protein in all cell types tested. To determine if the nuclear localization might result from increased antizyme-edAZIN affinity, we developed fluorescent protein FRET sensor for protein-protein interaction using Clover-AZIN and antizyme-mRuby2 fusion proteins. Unexpectedly, we found that the editing event modestly decreases edAZIN affinity for antizyme, notwithstanding increased interaction in vivo. Thus, the data indicate that the change in protein localization to the nucleus may be more important to oncogenic function than the actual degree of binding to antizyme. Other functional differences between edAZIN and AZIN might be explained by altered kinetics of binding, by the contribution of an additional adapter protein which modulates the intracellular antizyme:AZIN complex, or by competition for AZIN binding by other partners whose interaction is affected by the editing event. Finally, we identified AZIN and edAZIN interacting proteins by using tandem affinity purification and LC-MS-MS analysis. Among interacting proteins, we identified a complex containing two isoforms of nuclear actins (ACTG1 and ACTA2) and Myosin-9 that may be the driving force behind the nuclear shuttling of edAZIN. Citation Format: Aram Ghalali, James M. Rice, Liangzhe Wang, Chin Lee Wu, Michael S. Rogers, Bruce Zetter. Nuclear localization of antizyme inhibitor may be a marker for aggressiveness of prostate 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 4888.
Abstract 453: A circulating tumor cell assay for dynamic assessment of drug sensitivity in metastatic castration-resistant prostate cancer
Authors: Pai-Chi Teng, Yu Jen Jan, Junhee Yoon, Jie-Fu Chen, Pin-Jung Chen, Nu Yao, Shirley Cheng, Amber Lozano, Michael R. Freeman, Sungyong You, Hsian-Rong Tseng, Edwin M. Posadas
Journal: Cancer Research (2019)

Abstract Background: Tissue-based gene signatures can predict clinical behavior in prostate cancer (PC). Our objective was to extend their application to circulating tumor cells (CTCs) and to show that changes in the signature were associated with changes in clinical behavior. Methods: Our approach combined the Thermoresponsive(TR)-NanoVelcro CTC purification system with the Nanostring nCounter system for cellular purification and transcriptomic analysis. The Prostate Cancer Classification System (PCS) panel was modified for use in CTCs. We selected 31 blood samples from 23 PC patients receiving androgen receptor signaling inhibitors (ARSI) and measured the PCS1 Z score (probability). These findings were compared with clinical outcome data (responsiveness/resistance). Results: A modified, 16-gene PCS1 signature was established and validated through a rigorous bioinformatics process. We performed analytical validation of our combined CTC-RNA system to ensure reproducibility and specificity. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). The analyzed bloods contained samples from 8 patients who developed resistance to an ARSI allowing for dynamic measurement of gene expression. Our analysis found that the PCS1 Z score increased at the time that ARSI-resistance emerged (Pairwise T-test, P=0.016). Conclusions:Using this new methodology, contemporary, clinically-relevant gene signatures such as PCS could be measured non-invasively in CTCs. These findings can be used to relate gene expression to clinical drug response. This approach also allowed for measurement of dynamic variations of gene expression in individual patients over time that correlated to ARSI sensitivity. Citation Format: Pai-Chi Teng, Yu Jen Jan, Junhee Yoon, Jie-Fu Chen, Pin-Jung Chen, Nu Yao, Shirley Cheng, Amber Lozano, Michael R. Freeman, Sungyong You, Hsian-Rong Tseng, Edwin M. Posadas. A circulating tumor cell assay for dynamic assessment of drug sensitivity in metastatic castration-resistant prostate 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 453.
Abstract 3292: Prevalence and socio-behavioral determinants of psychological distress among cancer patients and survivors in the United States, 2010-2015
Authors: Gopal K. Singh, Lihua Liu, Audrey L. Chai, Alexander Ung, Michelle Allender
Journal: Cancer Research (2019)

Abstract Background: Cancer patients face many unique physical and mental health challenges that directly affect their cancer outcome and quality of life. As cancer treatment improves, the prevalence of long-term cancer survivors increases. However, the psychological well-being of cancer survivors has been largely understudied, which may lead to missed opportunities to improve cancer survivorship. Methods: Using 2010-2015 National Health Interview Surveys (N=194,757), we examined the prevalence of psychological distress among 17,657 adult cancer patients and survivors and identified the socio-demographic and behavioral correlates in the United States. Differentials in serious psychological distress (SPD, defined by a 6-item scale) and factor-based psychological distress scores (a composite index with a mean of 100 to measure levels of psychological distress) were analyzed by multivariate linear and logistic regression models. Results: The prevalence of SPD among cancer patients was 4.7% (95% CI: 4.2, 5.1), compared with 3.3% (95% CI: 3.1, 3.4) for the general population without a cancer history or diagnosis. The SPD prevalence was significantly higher among patients diagnosed with stomach, ovarian, cervical, and uterine cancers than the non-cancer population (age-adjusted odds ratio: 3.2, 3.1, 2.9, 2.7, respectively). Patients diagnosed with lung, colorectal, and thyroid cancer also reported significantly higher levels of psychological distress. SPD prevalence and distress index scores were substantially higher among American Indian/Alaska Native, Hispanic, and non-Hispanic (NH) Black cancer patients, compared with NH whites with cancer. Prevalence and levels of psychological distress were significantly greater among cancer patients with low education and income levels, non-professional occupations, unmarried status, functional limitation, and among smokers and physically inactive patients. Conclusions: Our findings underscore the importance of addressing the psychological well-being of cancer patients and survivors, particularly among the high-risk groups, in order to achieve the best treatment outcome and quality of life among the increasing number of cancer survivors. Citation Format: Gopal K. Singh, Lihua Liu, Audrey L. Chai, Alexander Ung, Michelle Allender. Prevalence and socio-behavioral determinants of psychological distress among cancer patients and survivors in the United States, 2010-2015 [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 3292.
Nonstandard first-line therapy and survival in patients (pts) with recurrent/metastatic head and neck cancer (RMHNSCC): Experience of 194 pts in a single institution.
Authors: Jerome Fayette, Valentine Polivka, Sylvie Chabaud, Bertrand Favier, Severine Racadot, Pascal Pommier, Xavier Montbarbon, Eve Marie Neidhardt, Didier Girodet, Philippe Zrounba
Journal: Journal of Clinical Oncology (2012)

e16036 Background: With the standard first line association platinum 5FU and cetuximab, median overall survival (OS) for RMHNSCC was 10.1 months (95% CI [8.6 – 11.2]) (N Engl J Med. 359:1116). Due to the toxicity of this treatment we often offer alternative therapy to our pts. This work aimed to evaluate impact of different 1st line treatment on OS. Methods: With the standard first line association platinum 5FU and cetuximab, median overall survival (OS) for RMHNSCC was 10.1 months (95% CI [8.6 – 11.2]) (N Engl J Med. 359:1116). Due to the toxicity of this treatment we often offer alternative therapy to our pts. This work aimed to evaluate impact of different 1st line treatment on OS. Results: At initiation of palliative chemotherapy, median age was 62 [29-87]; PS was 0, 1, 2, 3 in 13%, 59%, 16% and 11% of pts, respectively. First line chemotherapy consists in combination cisplatin+taxanes (CIST) 24%, caboplatin+taxanes (CART) 33%, cisplatin or carboplatin without taxanes (NOT) 15% or others (OTH) 28%. Median OS was estimated to 9.6 months CI95%=[8.1-11.4], with 39% of pts; CI95%=[32-47] still alive at 1-year. Second line of treatment has been initiated in 61% of pts. Some of them have even been able to have up to 3, 4 or more than 4 lines of treatment in 19%, 11% and 4% of pts, respectively. In the subgroup analysis, which represents a population similar to those included in [ref1], first line chemotherapy was CIST, CART, NOT or OTH in 30%, 30%, 18% and 22%, respectively. Median OS was 13.0 months, CI95%=[11.2-17.7] reaching up to 15.3 months for CIST subgroup. Second line of treatment was initiated in 73% of pts, with 20%, 15% and 5% of pts having a third, a fourth, and a fifth line, respectively. Conclusions: We can reach for unselected pts the best OS published in phase III studies. The use in first line of combination of platinum and taxanes, followed by monotherapies with cetuximab, capecitabine and methotrexate allows reaching OS of 13 months.
Abstract LB-078: New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody
Authors: Grace Zhou, Dongyao Ni, Runbin Yan, Xiaoqing Chen, Xianjie Liu, Jie Ma, Yuxin Tang
Journal: Cancer Research (2019)

Abstract Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpes simplex viruses (oHSV) have a major impact on cancer therapy marred by rare failures of healthy organs. Here we report the properties of 3 families of oHSV expressing no immunomodulatory genes (T1 series), murine or human IL-12 (T2 series) and murine or human IL-12 and anti-PD-1 antibody (T3 series). Thus insertion of the genes encoding PD-1 Ab and IL-12 significantly augmented the oncolytic activity of oHSV bereft of immune-stimulatory genes (T1 series). In syngeneic mice the murine T3 oHSV induced significant intratumoral accumulation of IL-12, PD-1 Ab and IFN-γ and was effective against a variety of murine tumors. Thus T3 oHSV concentrates the immunomodulatory products in the environment of the tumors thereby reducing the risk of toxicity associated with systemic administration. T3 oHSV injected into tumors was more effective than systemic administration of anti PD-1 Ab and IL12 alone or in combination with intratumoral injection of T1 oHSV. T3 induces local and systemic immune response characterized by cytokine signature. Citation Format: Grace Zhou, Dongyao Ni, Runbin Yan, Xiaoqing Chen, Xianjie Liu, Jie Ma, Yuxin Tang. New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody [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 LB-078.
Glucose Control in the Perioperative Period—Reply
Authors: Vinaya Simha, Pankaj Shah
Journal: JAMA (2019)

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Abstract LB-171: Global variation in prostate cancer incidence and mortality rates, 1980-2013
Authors: MaryBeth Freeman, Ahmedin Jemal
Journal: Cancer Research (2019)

Abstract Context: Previous studies documented significant international variation in prostate cancer rates due to differences in detection practices, availability of treatment, and genetic factors. Objective: To provide updated contemporary prostate cancer incidence and mortality patterns across five continents using the most recent cancer incidence data from the International Agency for Research on Cancer and mortality data from the World Health Organization (WHO). Evidence acquisition: We present estimated age-standardized prostate cancer incidence and mortality rates by country and WHO regions for 2012 based on GLOBOCAN. We examined long-term (1980 onwards) trends in prostate cancer incidence and mortality rates for 38 countries with high quality population-based incidence and mortality data. Trends were expressed as annual percent change using Joinpoint model. We also examined short-term (most recent 5 years) trends in prostate cancer among 44 countries with available incidence data and 71 countries with available mortality data. Evidence synthesis: The highest incidence rates during the most recent 5 years are found in Brazil, Lithuania, and Australia, whereas the lowest incidence rates are found in Asia (India, Thailand, and Bahrain). The highest mortality rates are found in the Caribbean (Barbados, Trinidad and Tobago, and Cuba), sub-Saharan Africa (South Africa), parts of former Soviet Union (Lithuania, Estonia, and Latvia), whereas the lowest rates are found in Asia (Thailand and Turkmenistan). Of the 44 countries with high quality incidence data, prostate cancer incidence rates during the most recent five data years increased in 4 countries (with Bulgaria showing the largest increase), decreased in 7 countries (with the biggest decrease in the United States), and stabilized in the remaining 31 countries. During the same time period, in contrast, among the 71 countries considered for the mortality trend, rates decreased in 14 countries, increased in 3 countries, and remained stable in 54 countries. Conclusions: In 2012, prostate cancer was the most commonly diagnosed cancer among men in 96 countries and the leading cause of death in 51 countries. In the most recent 5 years of data examined, prostate cancer incidence and mortality rates are decreasing or stabilizing in most parts of the world. Future studies should monitor trends in mortality rates and late-stage disease to assess the impact of reduction in PSA testing in several countries. Citation Format: MaryBeth Freeman, Ahmedin Jemal. Global variation in prostate cancer incidence and mortality rates, 1980-2013 [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 LB-171.
Abstract 890: Nuclear factor kappa B (NF-κB) promotes oxidative stress adaptation and survivorship
Authors: Elshaddai White, Jada R. Carter, Cimona V. Hinton
Journal: Cancer Research (2019)

Abstract Cellular oxidative stress is one of the several hallmarks of the aggressive phenotypes observed in prostate cancer. As levels of reactive oxygen species (ROS) increase, oxidative stressors activate mechanisms allowing cancer cells to adapt and survive. It is unclear how cancer cells adapt and survive oxidative stress; however, literature demonstrates that the transcription factor, nuclear factor-kappa B (NF-κB) contributes to survival during oxidative stress. In cancer, several factors resulting in oxidative stress, including chemotherapy, correlate with NF-κB expression and transcriptional activity, enhancing tumor survivorship and resistance to therapies. We examined adaptability and survivorship to oxidative stress in two common prostate cancer models, DU145 and PC3, which display varying degrees of tumorigenicity, respectively. We observed that serum-starvation induced ROS, stimulating an early oxidative stress environment, and cells further conferred adaptability with the addition of hydrogen peroxide (H202). Measurement of cell viability demonstrated a low death profile in stressed cells, while cell proliferation was stagnant. Quantitative measurement of apoptosis showed no significant cell death in stressed cells suggesting an adaptive mechanism to oxidative stress survival. Consistent with stress adaptation, we observed NF-κB in nuclear fractionations of cell lines which were consistent with nuclear localization observed in other diseases in literature that adapt to oxidative stress. Adaptability to oxidative stress may be a precursor to the inflammatory response in prostate tumor tissues, and/or a general survival mechanism to anti-tumorigenic agents. Acknowledgements: These studies were supported by the NIH/NIGMS/RISE #5R25GM060414-15 and NIH/NIHMD/RCMI #5G12MD007590. Citation Format: Elshaddai White, Jada R. Carter, Cimona V. Hinton. Nuclear factor kappa B (NF-κB) promotes oxidative stress adaptation and survivorship [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 890.
Effects of maternal medication on long-term outcome in congenital heart block remain to be established. Response to: ‘Comorbidity and long-term outcome in patients with congenital heart block and their siblings exposed to Ro/SSA autoantibodies in utero’ by Satis<i>et al</i>
Authors: Johannes Mofors, Sven-Erik Sonesson, Marie Wahren-Herlenius
Journal: Annals of the Rheumatic Diseases (2019)

We thank Satis and colleagues for opening the discussion on a potential influence of maternal immunomodulatory treatment on the long-term outcome of congenital heart block (CHB)1 and welcome their questions to help clarify some aspects of our study.2 Whether immunomodulatory treatment administered to the mother—as part of her own rheumatic disease treatment or intended to ameliorate the fetal cardiac inflammation in CHB—influences any outcome in CHB is a current matter of debate. Satis and colleagues cite several studies supporting a role …