SR9009 administered for one day after myocardial ischemia-reperfusion prevents heart failure in mice by targeting the cardiac inflammasome

Reperfusion of patients after myocardial infarction (heart attack) triggers cardiac inflammation that leads to infarct expansion and heart failure (HF). We previously showed that the circadian mechanism is a critical regulator of reperfusion injury. However, whether pharmacological targeting using circadian medicine limits reperfusion injury and protects against HF is unknown. Here, we show that short-term targeting of the circadian driver REV-ERB with SR9009 benefits long-term cardiac repair post-myocardial ischemia reperfusion in mice. Gain and loss of function studies demonstrate specificity of targeting REV-ERB in mice. Treatment for just one day abates the cardiac NLRP3 inflammasome, decreasing immunocyte recruitment, and thereby allowing the vulnerable infarct to heal. Therapy is given in vivo, after reperfusion, and promotes efficient repair. This study presents downregulation of the cardiac inflammasome in fibroblasts as a cellular target of SR9009, inviting more targeted therapeutic investigations in the future

The Impact of Sex, Circadian Disruption, and the Clock\u3csup\u3e∆19/∆19\u3c/sup\u3e Genotype on Alcohol Drinking in Mice

Shift work is associated with increased alcohol drinking, more so in males than females, and is thought to be a coping mechanism for disrupted sleep cycles. However, little is presently known about the causal influence of circadian rhythm disruptions on sex differences in alcohol consumption. In this study, we disrupted circadian rhythms in female and male mice using both environmental (i.e., shifting diurnal cycles) and genetic (i.e., Clock∆19/∆19 mutation) manipulations, and measured changes in alcohol consumption and preference using a two-bottle choice paradigm. Alcohol consumption and preference, as well as food and water consumption, total caloric intake, and weight were assessed in adult female and male Clock∆19/∆19 mutant mice or wild-type (WT) litter-mates, housed under a 12-hour:12-hour light:dark (L:D) cycle or a shortened 10-hour:10-hour L:D cycle. Female WT mice (under both light cycles) increased their alcohol consumption and preference over time, a pattern not observed in male WT mice. Compared to WT mice, Clock∆19/∆19 mice displayed increased alcohol consumption and preference. Sex differences were not apparent in Clock∆19/∆19 mice, with or without shifting diurnal cycles. In conclusion, sex differences in alcohol consumption patterns are evident and increase with prolonged access to alcohol. Disrupting circadian rhythms by mutating the Clock gene greatly increases alcohol consumption and abolishes sex differences present in WT animals

The Impact of Sex, Circadian Disruption, and the ClockΔ19/Δ19 Genotype on Alcohol Drinking in Mice

Shift work is associated with increased alcohol drinking, more so in males than females, and is thought to be a coping mechanism for disrupted sleep cycles. However, little is presently known about the causal influence of circadian rhythm disruptions on sex differences in alcohol consumption. In this study, we disrupted circadian rhythms in female and male mice using both environmental (i.e., shifting diurnal cycles) and genetic (i.e., ClockΔ19/Δ19 mutation) manipulations, and measured changes in alcohol consumption and preference using a two-bottle choice paradigm. Alcohol consumption and preference, as well as food and water consumption, total caloric intake, and weight were assessed in adult female and male ClockΔ19/Δ19 mutant mice or wild-type (WT) litter-mates, housed under a 12-hour:12-hour light:dark (L:D) cycle or a shortened 10-hour:10-hour L:D cycle. Female WT mice (under both light cycles) increased their alcohol consumption and preference over time, a pattern not observed in male WT mice. Compared to WT mice, ClockΔ19/Δ19 mice displayed increased alcohol consumption and preference. Sex differences were not apparent in ClockΔ19/Δ19 mice, with or without shifting diurnal cycles. In conclusion, sex differences in alcohol consumption patterns are evident and increase with prolonged access to alcohol. Disrupting circadian rhythms by mutating the Clock gene greatly increases alcohol consumption and abolishes sex differences present in WT animals

Cardiac contraction, calcium transients, and myofilament calcium sensitivity fluctuate with the estrous cycle in young adult female mice

This study established conditions to induce regular estrous cycles in female C57BL/6J mice and investigated the impact of the estrous cycle on contractions, Ca2+ transients, and underlying cardiac excitation-contraction (EC)-coupling mechanisms. Daily vaginal smears from group-housed virgin female mice were stained to distinguish estrous stage (proestrus, estrus, metestrus, diestrus). Ventricular myocytes were isolated from anesthetized mice. Contractions and Ca2+ transients were measured simultaneously (4 Hz, 37 °C). Interestingly, mice did not exhibit regular cycles unless they were exposed to male pheromones in bedding added to their cages. Field-stimulated myocytes from mice in estrus had larger contractions (∼2-fold increase), larger Ca2+ transients (∼1.11-fold increase), and longer action potentials (>2-fold increase) compared with other stages. Larger contractions and Ca2+ transients were not observed in estrus myocytes voltage-clamped with shorter action potentials. Voltage-clamp experiments also demonstrated that estrous stage had no effect on Ca2+ current, EC-coupling gain, diastolic Ca2+, sarcoplasmic reticulum (SR) Ca2+ content, or fractional release. Although contractions were largest in estrus, myofilament Ca2+ sensitivity was lowest (EC50 values ∼1.15-fold higher) in conjunction with increased phosphorylation of myosin binding protein C in estrus. Contractions were enhanced in ventricular myocytes from mice in estrus because action potential prolongation increased SR Ca2+ release. These findings demonstrate that cyclical changes in reproductive hormones associated with the estrous cycle can influence myocardial electrical and contractile function and modify Ca2+ homeostasis. However, such changes are unlikely to occur in female mice housed in groups under conventional conditions, since these mice do not exhibit regular estrous cycles

Proceedings Of The 7Th Biannual International Symposium On Nasopharyngeal Carcinoma 2015

A1 Hope and despair in the current treatment of nasopharyngeal cancer, IB Tan, I1 NPC international incidence and risk factors, Ellen T Chang, I2 Familial nasopharyngeal carcinoma and the use of biomarkers, Chien-Jen Chen, Wan-Lun Hsu, Yin-Chu Chien, I3 Genetic susceptibility risk factors for sporadic and familial NPC: recent findings, Allan Hildesheim, I5 Genetic and environmental risk factors for nasopharyngeal cancer in Southeast Asia, James D McKay, Valerie Gaborieau, Mohamed Arifin Bin Kaderi, Dewajani Purnomosari, Catherine Voegele, Florence LeCalvez-Kelm, Graham Byrnes, Paul Brennan, Beena Devi, I6 Characterization of the NPC methylome identifies aberrant epigenetic disruption of key signaling pathways and EBV-induced gene methylation, Li L, Zhang Y, Fan Y, Sun K, Du Z, Sun H, Chan AT, Tsao SW, Zeng YX, Tao Q, I7 Tumor exosomes and translational research in NPC, Pierre Busson, Claire Lhuillier, Olivier Morales, Dhafer Mrizak, Aurore Gelin, Nikiforos Kapetanakis, Nadira Delhem, I8 Host manipulations of the Epstein-Barr virus EBNA1 protein, Sheila Mansouri, Jennifer Cao, Anup Vaidya, and Lori Frappier, I9 Somatic genetic changes in EBV-associated nasopharyngeal carcinoma, Lo Kwok Wai, I10 Preliminary screening results for nasopharyngeal carcinoma with ELISA-based EBV antibodies in Southern China, Sui-Hong Chen, Jin-lin Du, Ming-Fang Ji, Qi-Hong Huang, Qing Liu, Su-Mei Cao, I11 EBV array platform to screen for EBV antibodies associated with NPC and other EBV-associated disorders, Denise L. Doolan, Anna Coghill, Jason Mulvenna, Carla Proietti, Lea Lekieffre, Jeffrey Bethony, and Allan Hildesheim, I12 The nasopharyngeal carcinoma awareness program in Indonesia, Renske Fles, Sagung Rai Indrasari, Camelia Herdini, Santi Martini, Atoillah Isfandiari, Achmad Rhomdoni, Marlinda Adham, Ika Mayangsari, Erik van Werkhoven, Maarten Wildeman, Bambang Hariwiyanto, Bambang Hermani, Widodo Ario Kentjono, Sofia Mubarika Haryana, Marjanka Schmidt, IB Tan, I13 Current advances and future direction in nasopharyngeal cancer management, Brian O’Sullivan, I14 Management of juvenile nasopharyngeal cancer, Enis Ozyar, I15 Global pattern of nasopharyngeal cancer: correlation of outcome with access to radiotherapy, Anne WM Lee, I16 The predictive/prognostic biomarker for nasopharyngeal carcinoma, Mu-Sheng Zeng, I17 Effect of HLA and KIR polymorphism on NPC risk, Xiaojiang Gao, Minzhong Tang, Pat Martin, Yi Zeng, Mary Carrington, I18 Exploring the Association between Potentially Neutralizing Antibodies against EBV Infection and Nasopharyngeal Carcinoma, Anna E Coghill, Wei Bu, Hanh Nguyen, Wan-Lun Hsu, Kelly J Yu, Pei-Jen Lou, Cheng-Ping Wang, Chien-Jen Chen, Allan Hildesheim, Jeffrey I Cohen, I19 Advances in MR imaging in NPC, Ann D King, O1 Epstein-Barr virus seromarkers and risk of nasopharyngeal carcinoma: the gene-environment interaction study on nasopharyngeal carcinoma in Taiwan, Yin-Chu Chien, Wan-Lun Hsu, Kelly J Yu, Tseng-Cheng Chen, Ching-Yuan Lin, Yung-An Tsou, Yi-Shing Leu, Li-Jen Laio, Yen-Liang Chang, Cheng-Ping Wang, Chun-Hun Hua, Ming-Shiang Wu, Chu-Hsing Kate Hsiao, Jehn-Chuan Lee, Ming-Hsui Tsai, Skye Hung-Chun Cheng, Pei-Jen Lou, Allan Hildesheim, Chien-Jen Chen, O2 Familial tendency and environmental co-factors of nasopharyngeal carcinoma: the gene-environment interaction study on nasopharyngeal carcinoma in Taiwan, Wan-Lun Hsu, Kelly J Yu, Yin-Chu Chien, Tseng-Cheng Chen, Ching-Yuan Lin, Yung-An Tsou, Yi-Shing Leu, Li-Jen Liao, Yen-Liang Chang, Tsung-Lin Yang, Chun-Hun Hua, Ming-ShiangWu, Chu-Hsing Kate Hsiao, Jehn-ChuanLee, Ming-Hsui Tsai, Skye Hung-Chun Cheng, Jenq-Yuh Ko, Allan Hildesheim, Chien-Jen Chen, O3 The genetic susceptibility and prognostic role of TERT-CLPTM1L and genes in DNA damage pathways in NPC, Josephine Mun Yee Ko, Wei Dai, Dora Kwong, Wai Tong Ng, Anne Lee, Roger Kai Cheong Ngan, Chun Chung Yau, Stewart Tung, Maria Li Lung, O4 Long term effects of NPC screening, Mingfang Ji, Wei Sheng, Mun Hon Ng, Weimin Cheng, Xia Yu, Biaohua Wu, Kuangrong Wei, Jun Zhan, Yi Xin Zeng, Su Mei Cao, Ningshao Xia, Yong Yuan, O5 Risk prediction of nasopharyngeal carcinoma by detecting host genetic and Epstein-Barr virus variation in saliva, Qian Cui, Miao Xu, Jin-Xin Bei, Yi-Xin Zeng, O6 Patterns of care study in Turkish nasopharyngeal cancer patients (NAZOTURK): A Turkish Radiation Oncology Association Head and Neck Cancer Working Group Study, B Şahin, A Dizman, M Esassolak, A Saran İkizler, HC Yıldırım, M Çaloğlu, B Atalar, F Akman, C Demiroz, BM Atasoy, E Canyilmaz, S Igdem, G Ugurluer, T Kütük, M Akmansoy, E Ozyar, O7 Long term outcome of intensity modulated radiotherapy in nasopharyngeal carcinoma in National Cancer Centre Singapore, Kiattisa Sommat, Fu Qiang Wang, Li-Lian Kwok, Terence Tan, Kam Weng Fong, Yoke Lim Soong, Shie Lee Cheah, Joseph Wee, O8 International phase II randomized study on the addition of docetaxel to the combination of cisplatin and 5-fluorouracil in the induction treatment for nasopharyngeal carcinoma in children and adolescents, M Casanova, E Özyar, C Patte, D Orbach, A Ferrari, VF Cristine, H Errihani, J Pan, L Zhang, S Liji, K Grzegorzewski, L Gore, A Varan, O9 Prognostic impact of metastatic status in patients with nasopharyngeal carcinoma, Susanna Hilda Hutajulu, Guntara Khuzairi, Camelia Herdini, Henry Kusumo, Mardiah Suci Hardianti, Kartika Widayati Taroeno-Hariadi, Ibnu Purwanto, Johan Kurnianda, O10 Development of small molecule inhibitors of latent Epstein-Barr virus infection for the treatment of nasopharyngeal carcinoma, Troy E. Messick, Kimberly Malecka, Lois Tolvinski, Samantha Soldan, Julianna Deakyne, Hui Song, Antonio van den Heuvel, Baiwei Gu, Joel Cassel, Mark McDonnell, Garry R Smith, Venkata Velvadapu, Haiyan Bian, Yan Zhang, Marianne Carlsen, Shuai Chen, Alastair Donald, Christian Lemmen, Allen B Reitz, Paul M Lieberman, O11 Therapeutic targeting of cancer stem-like cells using a Wnt modulator, ICG-001, enhances the treatment outcome of EBV-positive nasopharyngeal carcinoma, King Chi Chan, Lai Sheung Chan, Kwok Wai Lo, Timothy Tak Chun Yip, Roger Kai Cheong Ngan, Michael Kahn, Maria Li Lung, Nai Ki Mak, O12 Role of micro-RNA in NPC biology, Fei-Fei Liu, O13 Expansion of EBNA1- and LMP2-specific effector T lymphocytes from patients with nasopharyngeal carcinoma without enhancement of regulatory T cells, Wafa Khaali; Juliette Thariat; Laurence Fantin; Flavia Spirito; Meriem Khyatti; El Khalil Ben Driss; Sylvain Olivero; Janet Maryanski; Alain Doglio, O14 The experience of patients’ life after amifostine radiotherapy treatment (ART) for nasopharyngeal carcinoma (NPC), Mengxue Xia, Yunfei Xia, Hui Chang, Rachel Shaw, O15 Analysis of mitochondrial DNA mutation in latent membrane protein-1 positive nasopharyngeal carcinoma, Pudji Rahaju, O16 Factors influencing treatment adherence of nasopharyngeal cancer and the clinical outcomes: a hospital-based study, Mardiah Suci Hardianti, Sindhu Wisesa, Kartika Widayati Taroeno-Harijadi, Ibnu Purwanto, Bambang Hariwiyanto, Wigati Dhamiyati, Johan Kurnianda, O17 Chromosomal breaks mediated by bile acid-induced apoptosis in nasopharyngeal epithelial cells: in relation to matrix association region/scaffold attachment region, Sang-Nee Tan, Sai-Peng Sim, O18 Expression of p53 (wild type) on nasopharyngeal carcinoma stem cell that resistant to radiotherapy, Muhtarum Yusuf, Ahmad C Romdhoni, Widodo Ario K, Fedik Abdul Rantam, O19 Mathematical model of nasopharyngeal carcinoma in cellular level, Sugiyanto, Lina Aryati, Fajar Adi-Kusumo, Mardiah Suci Hardianti, O20 Differential expression of microRNA-21 on nasopharyngeal carcinoma plasma patient, SY Bintoro, R Oktriani, C. Herawati, A Surono, Sofia M. Haryana, O21 Therapeutic targeting of an oncogenic fibroblast growth factor-FGF19, which promotes proliferation and induces EMT of carcinoma cells through activating ERK and AKT signaling, L. Zhong, L. Li, B. B. Ma, A. T. Chan, Q. Tao, O22 Resist nasopharyngeal carcinoma (NPC): next generation T cells for the adoptive immunotherapy of NPC, M. Kalra, M. Ngo, S. Perna, A. Leen, N. Lapteva, C. M. Rooney, S. Gottschalk, O23 The correlation of heat shock protein 70 expressions and staging of nasopharyngeal carcinoma, Elida Mustikaningtyas, Sri Herawati, Achmad C Romdhoni, O24 Epstein-Barr virus serological profiles of nasopharyngeal carcinoma - A tribute to Werner Henle, Mingfang Ji, YaruiXu, Weimin Cheng, ShengxiangGe, Fugui Li, M. H. Ng, O25 Targeting the apoptosis pathway using combination TLR3 agonist with anti-survivin molecule (YM-155) in nasopharyngeal carcinoma, Louise SY Tan, Benjamin Wong, CM Lim, O26 The resistance mechanism of nasopharyngeal cancer stem cells to cisplatin through expression of CD44, Hsp70, p53 (wild type), Oct-4, and ß-catenin encoded-genes, Achmad C Romdhoni, Fedik A. Rantam, Widodo Ario Kentjono, P1 Prevalence of nasopharyngeal carcinoma patients at Departement of Otorhinolaringology-Head and Neck Surgery, Dr. Hasan Sadikin general hospital, Bandung, Indonesia in 2010-2014, Deasy Z Madani, Nur Akbar, Agung Dinasti Permana, P2 Case report on pediatric nasopharyngeal carcinoma at Dr. Sardjito Hospital, Yogyakarta, Camelia Herdini, Sagung Rai Indrasari, Jajah Fachiroh, Dwi Hartati, T. Baning Rahayudjati, P3 Report on loco regionally advanced nasopharyngeal cancer patients treated with induction chemotherapy followed by concurrent chemo-radiation therapy, Iswandi Darwis, Susanna Hilda Hutajulu, Bambang Hariwiyanto, Wigati Dhamiyati, Ibnu Purwanto, Kartika Widayati Taroeno-Hariadi, Johan Kurnianda, P4 Sex and age differences in the survival of patients with nasopharyngeal carcinoma, Sindhu Wisesa, Mardiah Suci Hardianti, Susanna Hilda Hutajulu, Kartika Widayati Taroeno-Harijadi, Ibnu Purwanto, Camelia Herdini, Wigati Dhamiyati, Johan Kurnianda, P5 Impact of delayed diagnosis and delayed therapy in the treatment outcome of patients with nasopharyngeal carcinoma, Khoirul Anwar, Susanna Hilda Hutajulu, Sagung Rai Indrasari, Sri Retna Dwidanarti, Ibnu Purwanto, Kartika Widayati Taroeno-Hariadi, Johan Kurnianda, P6 Anaysis of pretreatment anemia in nasopharyngeal cancer patients undergoing neoadjuvant therapy, Dominicus Wendhy Pramana, Susanna Hilda Hutajulu, Bambang Hariwiyanto, Wigati Dhamiyati, Ibnu Purwanto, Kartika Widayati Taroeno-Hariadi, Johan Kurnianda, P7 Results of treatment with neoadjuvant cisplatin-5FU in locally advanced nasopharyngeal carcinoma: a local experience, Diah Ari Safitri, Susanna Hilda Hutajulu, Camelia Herdini, Sri Retna Dwi Danarti, Ibnu Purwanto, Kartika Widayati Taroeno-Hariadi, Johan Kurnianda, P8 Geriatrics with nasopharyngeal cancer, Suryo A Taroeno, Sindhu Wisesa, Kartika Widayati Taroeno-Hariadi, Ibnu Purwanto, Bambang Hariwiyanto, Wigati Dhamiyati, Johan Kurnianda, P9 Correlation of lymphocyte to monocyte and neutrophil to lymphocyte ratio to the response of cisplatin chemoradiotheraphy in locally advance nasopharyngeal carcinoma, I. Wijaya, A. Oehadian, D. Prasetya, P10 Prediction of nasopharyngeal carcinoma risk by Epstein-Barr virus seromarkers and environmental co-factors: the gene-environment interaction study on nasopharyngeal carcinoma in Taiwan, Wan-Lun Hsu, Yin-Chu Chien, Kelly J Yu, Cheng-Ping Wang, Ching-Yuan Lin, Yung-An Tsou, Yi-Shing Leu, Li-Jen Liao, Yen-Liang Chang191,192, Jenq-Yuh Ko, Chun-Hun Hua, Ming-Shiang Wu, Chu-Hsing Kate Hsiao, Jehn-Chuan Lee, Ming-Hsui Tsai, Skye Hung-Chun Cheng, Pei-Jen Lou, Allan Hildesheim, Chien-Jen Chen, P11 Non-viral risk factors for nasopharyngeal carcinoma in West Sumatra, Indonesia, Sukri Rahman, Bestari J. Budiman, Novialdi, Rahmadona, Dewi Yuri Lestari, P12 New prototype Vidas EBV IgA quick: performance on Chinese and Moroccan populations, C. Yin, A. Foussadier, E. Blein, C. Chen, N. Bournet Ammour, M. Khiatti, S. Cao, P13 The expression of EBV-LMP1 and VEGF as predictors and plasma EBV-DNA levels as early marker of distant metastasis after therapy in nasopharyngeal cancer, Dewi Syafriyetti Soeis Marzaini, P14 Characteristics and factors influencing subjects refusal for blood samples retrieval: lesson from NPC case control study in Yogyakarta – Indonesia, Dwi Hartati, Baning Rahayujati, Camelia Herdini, Jajah Fachiroh, P15 Expression of microRNA BART-7-3p and mRNA PTEN on blood plasma of patients with nasopharyngeal carcinoma, L. Gunawan, S. Mubarika Haryana, A. Surono, C. Herawati, P16 IgA response to native early antigen (IgA-EAext) of Epstein-Barr virus (EBV) in healthy population and nasopharyngeal carcinoma (NPC) patients: the potential for diagnosis and screening tools, Michael Hartono, Jajah Fachiroh, Umi Intansari, Dewi Kartikawati Paramita, P17 IgA responses against Epstein-Barr Virus Early Antigen (EBV-EA) peptides as potential candidates of nasopharyngeal carcinoma detection marker, Akmal Akbar, Jajah Fachiroh, Dewi Kartikawati Paramita, P18 Association between smoking habit and IgA-EBV titer among healthy individuals in Yogyakarta, Indonesia, Benny Hermawan, T Baning Rahayudjati, Dewi K Paramita, Jajah Fachiroh, P19 Epstein-Barr virus IgA titer comparison of healthy non-family individuals and healthy first degree family of NPV patients, Gabriella Argy, Jajah Fachiroh, Dewi Kartikawati Paramita, Susanna Hilda Hutajulu, P20 Identification of EBV Early Antigen (EA) derived peptides for NPC diagnosis, Theodora Caroline Sihotang, Jajah Fachiroh, Umi Intansari, Dewi Kartikawati Paramita, P21 Host-pathogen study: relative expression of mRNA BRLF1 Epstein-Barr virus as a potential biomarker for tumor progressivity and polymorphisms of TCRBC and TCRGC2 host genes related to genetic susceptibility on nasopharyngeal carcinoma, Daniel Joko Wahyono, Purnomo Soeharso, Dwi Anita Suryandari, Lisnawati, Zanil Musa, Bambang Hermani, P22 In vitro efficacy of silvestrol and episilvestrol, isolated from Borneo, on nasopharyngeal carcinoma, a major cancer in Borneo, Maelinda Daker, Yeo Jiun Tzen, Norhasimah Bakar, Asma’ Saiyidatina Aishah Abdul Rahman, Munirah Ahmad, Yeo Tiong Chia, Alan Khoo Soo Beng, P23 The expression of mir-141 in patients with nasopharyngeal cancer, Widyandani Sasikirana, Tirta Wardana, Muhammad Radifar, Cita Herawati, Agus Surono, Sofia Mubarika HaryanaPubMe