Publications by authors named "Dara K Mohammad"

18 Publications

  • Page 1 of 1

Short-term IL-15 priming leaves a long-lasting signalling imprint in mouse NK cells independently of a metabolic switch.

Life Sci Alliance 2021 04 16;4(4). Epub 2021 Feb 16.

Department of Medicine Huddinge, Centre for Haematology and Regenerative Medicine (HERM), Karolinska Institutet, Huddinge, Sweden

IL-15 priming of NK cells is a broadly accepted concept, but the dynamics and underlying molecular mechanisms remain poorly understood. We show that as little as 5 min of IL-15 treatment in vitro, followed by removal of excess cytokines, results in a long-lasting, but reversible, augmentation of NK cell responsiveness upon activating receptor cross-linking. In contrast to long-term stimulation, improved NK cell function after short-term IL-15 priming was not associated with enhanced metabolism but was based on the increased steady-state phosphorylation level of signalling molecules downstream of activating receptors. Inhibition of JAK3 eliminated this priming effect, suggesting a cross talk between the IL-15 receptor and ITAM-dependent activating receptors. Increased signalling molecule phosphorylation levels, calcium flux, and IFN-γ secretion lasted for up to 3 h after IL-15 stimulation before returning to baseline. We conclude that IL-15 rapidly and reversibly primes NK cell function by modulating activating receptor signalling. Our findings suggest a mechanism by which NK cell reactivity can potentially be maintained in vivo based on only brief encounters with IL-15 trans-presenting cells.
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http://dx.doi.org/10.26508/lsa.202000723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918643PMC
April 2021

BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib.

Leukemia 2021 Feb 1. Epub 2021 Feb 1.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86, Huddinge, Sweden.

Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the "gatekeeper" residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.
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http://dx.doi.org/10.1038/s41375-021-01123-6DOI Listing
February 2021

Cardiac, Hepatic and Renal Dysfunction and IL-18 Polymorphism in Breast, Colorectal, and Prostate Cancer Patients.

Asian Pac J Cancer Prev 2021 Jan 1;22(1):131-137. Epub 2021 Jan 1.

Department of Biology, College of Science, Salahaddin University-Erbil, Kurdistan Region, Iraq.

Introduction: The present study aimed to determine the alterations in the serum levels of tumor markers used to evaluate cardiac, renal and liver function, and detect the interleukin (IL)-18 rs1946518 polymorphism in breast (BC), colorectal (CRC) and prostate cancer (PCa) patients.

Methods: Blood samples were collected from 65 female BC, 116 CRC, 79 PCa and 88 myocardial infarction (MI) patients, and 110 healthy individuals to determine the concentration of tumor and cardiac markers. Furthermore, the IL-18 rs1946518 polymorphism was assessed using amplification refractory mutation system (ARMS)-PCR.

Results: The serum levels of the tumor markers cancer antigen 15-3 (CA 15-3), carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) and total prostate-specific antigen (TPSA) were significantly increased in cancer patients compared with healthy controls. Furthermore, the activity of high-sensitivity cardiac troponin T (hs-cTnT) and creatine kinase‑myocardial band (CK-MB) was enhanced in MI patients, however, their activity was unchanged in cancer patients. The activity of alkaline phosphatase (ALP), and the serum concentration of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and urea were markedly elevated in CRC and PCa patients, respectively, compared with the control group. Although, no significant differences were observed in the -607 C/A polymorphism and allele frequency of IL-18 among BC, CRC patients and healthy individuals, the odds ratio (OR) was 1.75 for both C and A allele in BC patients. Therefore, the -607 C/A polymorphism could be considered as a risk factor for BC.

Conclusion: The aforementioned results suggested that tumor markers could be considered as excellent biomarkers for the early detection of BC, CRC and PCa, whereas the concentration of liver enzymes could serve as an alternative indicator for the diagnosis of CRC and PCa. Additionally, the rs1946518 polymorphism in the IL-18 gene could be considered as a risk factor for the occurrence of BC, CRC and PCa.
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http://dx.doi.org/10.31557/APJCP.2021.22.1.131DOI Listing
January 2021

The kidney injury caused by the onset of acute graft-versus-host disease is associated with down-regulation of αKlotho.

Int Immunopharmacol 2020 Jan 4;78:106042. Epub 2019 Dec 4.

Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Stockholm 141 86, Sweden. Electronic address:

Acute graft-versus-host disease (aGVHD) and kidney injury are the major complications after allogeneic hematopoietic stem cell transplantation (HSCT). Although the underlying mechanisms for the development of these complications are not yet fully understood, it has been proposed that emergence of aGVHD contributes to the development of kidney injury after HSCT. We have shown previously that aGVHD targets the kidney in a biphasic manner: at the onset, inflammatory genes are up-regulated, while when aGVHD becomes established, donor lymphocytes infiltrate the kidney. Here, we characterize renal manifestations at the onset of aGVHD. Mice receiving allogeneic bone marrow and spleen cells displayed symptoms of aGVHD and elevated serum levels of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) within 4 days. There was concurrent kidney injury with the following characteristics: (1) elevated expression of the kidney injury biomarker, neutrophil gelatinase-associated lipocalin (NGAL), (2) accumulation of hetero-lysosomes in proximal tubule epithelial cells, and (3) reductions in αKlotho mRNA and protein and increased serum levels of fibroblast growth factor 23 (Fgf23), phosphate and urea. This situation resembled acute renal injury caused by bacterial lipopolysaccharide. We conclude that the onset of aGVHD is associated with kidney injury involving down-regulation of αKlotho, a sight that may inspire novel therapeutic approaches.
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http://dx.doi.org/10.1016/j.intimp.2019.106042DOI Listing
January 2020

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017.

Authors:
Roy Burstein Nathaniel J Henry Michael L Collison Laurie B Marczak Amber Sligar Stefanie Watson Neal Marquez Mahdieh Abbasalizad-Farhangi Masoumeh Abbasi Foad Abd-Allah Amir Abdoli Mohammad Abdollahi Ibrahim Abdollahpour Rizwan Suliankatchi Abdulkader Michael R M Abrigo Dilaram Acharya Oladimeji M Adebayo Victor Adekanmbi Davoud Adham Mahdi Afshari Mohammad Aghaali Keivan Ahmadi Mehdi Ahmadi Ehsan Ahmadpour Rushdia Ahmed Chalachew Genet Akal Joshua O Akinyemi Fares Alahdab Noore Alam Genet Melak Alamene Kefyalew Addis Alene Mehran Alijanzadeh Cyrus Alinia Vahid Alipour Syed Mohamed Aljunid Mohammed J Almalki Hesham M Al-Mekhlafi Khalid Altirkawi Nelson Alvis-Guzman Adeladza Kofi Amegah Saeed Amini Arianna Maever Loreche Amit Zohreh Anbari Sofia Androudi Mina Anjomshoa Fereshteh Ansari Carl Abelardo T Antonio Jalal Arabloo Zohreh Arefi Olatunde Aremu Bahram Armoon Amit Arora Al Artaman Anvar Asadi Mehran Asadi-Aliabadi Amir Ashraf-Ganjouei Reza Assadi Bahar Ataeinia Sachin R Atre Beatriz Paulina Ayala Quintanilla Martin Amogre Ayanore Samad Azari Ebrahim Babaee Arefeh Babazadeh Alaa Badawi Soghra Bagheri Mojtaba Bagherzadeh Nafiseh Baheiraei Abbas Balouchi Aleksandra Barac Quique Bassat Bernhard T Baune Mohsen Bayati Neeraj Bedi Ettore Beghi Masoud Behzadifar Meysam Behzadifar Yared Belete Belay Brent Bell Michelle L Bell Dessalegn Ajema Berbada Robert S Bernstein Natalia V Bhattacharjee Suraj Bhattarai Zulfiqar A Bhutta Ali Bijani Somayeh Bohlouli Nicholas J K Breitborde Gabrielle Britton Annie J Browne Sharath Burugina Nagaraja Reinhard Busse Zahid A Butt Josip Car Rosario Cárdenas Carlos A Castañeda-Orjuela Ester Cerin Wagaye Fentahun Chanie Pranab Chatterjee Dinh-Toi Chu Cyrus Cooper Vera M Costa Koustuv Dalal Lalit Dandona Rakhi Dandona Farah Daoud Ahmad Daryani Rajat Das Gupta Ian Davis Nicole Davis Weaver Dragos Virgil Davitoiu Jan-Walter De Neve Feleke Mekonnen Demeke Gebre Teklemariam Demoz Kebede Deribe Rupak Desai Aniruddha Deshpande Hanna Demelash Desyibelew Sagnik Dey Samath Dhamminda Dharmaratne Meghnath Dhimal Daniel Diaz Leila Doshmangir Andre R Duraes Laura Dwyer-Lindgren Lucas Earl Roya Ebrahimi Soheil Ebrahimpour Andem Effiong Aziz Eftekhari Elham Ehsani-Chimeh Iman El Sayed Maysaa El Sayed Zaki Maha El Tantawi Ziad El-Khatib Mohammad Hassan Emamian Shymaa Enany Sharareh Eskandarieh Oghenowede Eyawo Maha Ezalarab Mahbobeh Faramarzi Mohammad Fareed Roghiyeh Faridnia Andre Faro Ali Akbar Fazaeli Mehdi Fazlzadeh Netsanet Fentahun Seyed-Mohammad Fereshtehnejad João C Fernandes Irina Filip Florian Fischer Nataliya A Foigt Masoud Foroutan Joel Msafiri Francis Takeshi Fukumoto Nancy Fullman Silvano Gallus Destallem Gebremedhin Gebre Tsegaye Tewelde Gebrehiwot Gebreamlak Gebremedhn Gebremeskel Bradford D Gessner Birhanu Geta Peter W Gething Reza Ghadimi Keyghobad Ghadiri Mahsa Ghajarzadeh Ahmad Ghashghaee Paramjit Singh Gill Tiffany K Gill Nick Golding Nelson G M Gomes Philimon N Gona Sameer Vali Gopalani Giuseppe Gorini Bárbara Niegia Garcia Goulart Nicholas Graetz Felix Greaves Manfred S Green Yuming Guo Arvin Haj-Mirzaian Arya Haj-Mirzaian Brian James Hall Samer Hamidi Hamidreza Haririan Josep Maria Haro Milad Hasankhani Edris Hasanpoor Amir Hasanzadeh Hadi Hassankhani Hamid Yimam Hassen Mohamed I Hegazy Delia Hendrie Fatemeh Heydarpour Thomas R Hird Chi Linh Hoang Gillian Hollerich Enayatollah Homaie Rad Mojtaba Hoseini-Ghahfarokhi Naznin Hossain Mostafa Hosseini Mehdi Hosseinzadeh Mihaela Hostiuc Sorin Hostiuc Mowafa Househ Mohamed Hsairi Olayinka Stephen Ilesanmi Mohammad Hasan Imani-Nasab Usman Iqbal Seyed Sina Naghibi Irvani Nazrul Islam Sheikh Mohammed Shariful Islam Mikk Jürisson Nader Jafari Balalami Amir Jalali Javad Javidnia Achala Upendra Jayatilleke Ensiyeh Jenabi John S Ji Yash B Jobanputra Kimberly Johnson Jost B Jonas Zahra Jorjoran Shushtari Jacek Jerzy Jozwiak Ali Kabir Amaha Kahsay Hamed Kalani Rohollah Kalhor Manoochehr Karami Surendra Karki Amir Kasaeian Nicholas J Kassebaum Peter Njenga Keiyoro Grant Rodgers Kemp Roghayeh Khabiri Yousef Saleh Khader Morteza Abdullatif Khafaie Ejaz Ahmad Khan Junaid Khan Muhammad Shahzeb Khan Young-Ho Khang Khaled Khatab Amir Khater Mona M Khater Alireza Khatony Mohammad Khazaei Salman Khazaei Maryam Khazaei-Pool Jagdish Khubchandani Neda Kianipour Yun Jin Kim Ruth W Kimokoti Damaris K Kinyoki Adnan Kisa Sezer Kisa Tufa Kolola Soewarta Kosen Parvaiz A Koul Ai Koyanagi Moritz U G Kraemer Kewal Krishan Kris J Krohn Nuworza Kugbey G Anil Kumar Manasi Kumar Pushpendra Kumar Desmond Kuupiel Ben Lacey Sheetal D Lad Faris Hasan Lami Anders O Larsson Paul H Lee Mostafa Leili Aubrey J Levine Shanshan Li Lee-Ling Lim Stefan Listl Joshua Longbottom Jaifred Christian F Lopez Stefan Lorkowski Sameh Magdeldin Hassan Magdy Abd El Razek Muhammed Magdy Abd El Razek Azeem Majeed Afshin Maleki Reza Malekzadeh Deborah Carvalho Malta Abdullah A Mamun Navid Manafi Ana-Laura Manda Morteza Mansourian Francisco Rogerlândio Martins-Melo Anthony Masaka Benjamin Ballard Massenburg Pallab K Maulik Benjamin K Mayala Mohsen Mazidi Martin McKee Ravi Mehrotra Kala M Mehta Gebrekiros Gebremichael Meles Walter Mendoza Ritesh G Menezes Atte Meretoja Tuomo J Meretoja Tomislav Mestrovic Ted R Miller Molly K Miller-Petrie Edward J Mills George J Milne G K Mini Seyed Mostafa Mir Hamed Mirjalali Erkin M Mirrakhimov Efat Mohamadi Dara K Mohammad Aso Mohammad Darwesh Naser Mohammad Gholi Mezerji Ammas Siraj Mohammed Shafiu Mohammed Ali H Mokdad Mariam Molokhia Lorenzo Monasta Yoshan Moodley Mahmood Moosazadeh Ghobad Moradi Masoud Moradi Yousef Moradi Maziar Moradi-Lakeh Mehdi Moradinazar Paula Moraga Lidia Morawska Abbas Mosapour Seyyed Meysam Mousavi Ulrich Otto Mueller Atalay Goshu Muluneh Ghulam Mustafa Behnam Nabavizadeh Mehdi Naderi Ahamarshan Jayaraman Nagarajan Azin Nahvijou Farid Najafi Vinay Nangia Duduzile Edith Ndwandwe Nahid Neamati Ionut Negoi Ruxandra Irina Negoi Josephine W Ngunjiri Huong Lan Thi Nguyen Long Hoang Nguyen Son Hoang Nguyen Katie R Nielsen Dina Nur Anggraini Ningrum Yirga Legesse Nirayo Molly R Nixon Chukwudi A Nnaji Marzieh Nojomi Mehdi Noroozi Shirin Nosratnejad Jean Jacques Noubiap Soraya Nouraei Motlagh Richard Ofori-Asenso Felix Akpojene Ogbo Kelechi E Oladimeji Andrew T Olagunju Meysam Olfatifar Solomon Olum Bolajoko Olubukunola Olusanya Mojisola Morenike Oluwasanu Obinna E Onwujekwe Eyal Oren Doris D V Ortega-Altamirano Alberto Ortiz Osayomwanbo Osarenotor Frank B Osei Aaron E Osgood-Zimmerman Stanislav S Otstavnov Mayowa Ojo Owolabi Mahesh P A Abdol Sattar Pagheh Smita Pakhale Songhomitra Panda-Jonas Animika Pandey Eun-Kee Park Hadi Parsian Tahereh Pashaei Sangram Kishor Patel Veincent Christian Filipino Pepito Alexandre Pereira Samantha Perkins Brandon V Pickering Thomas Pilgrim Majid Pirestani Bakhtiar Piroozi Meghdad Pirsaheb Oleguer Plana-Ripoll Hadi Pourjafar Parul Puri Mostafa Qorbani Hedley Quintana Mohammad Rabiee Navid Rabiee Amir Radfar Alireza Rafiei Fakher Rahim Zohreh Rahimi Vafa Rahimi-Movaghar Shadi Rahimzadeh Fatemeh Rajati Sree Bhushan Raju Azra Ramezankhani Chhabi Lal Ranabhat Davide Rasella Vahid Rashedi Lal Rawal Robert C Reiner Andre M N Renzaho Satar Rezaei Aziz Rezapour Seyed Mohammad Riahi Ana Isabel Ribeiro Leonardo Roever Elias Merdassa Roro Max Roser Gholamreza Roshandel Daem Roshani Ali Rostami Enrico Rubagotti Salvatore Rubino Siamak Sabour Nafis Sadat Ehsan Sadeghi Reza Saeedi Yahya Safari Roya Safari-Faramani Mahdi Safdarian Amirhossein Sahebkar Mohammad Reza Salahshoor Nasir Salam Payman Salamati Farkhonde Salehi Saleh Salehi Zahabi Yahya Salimi Hamideh Salimzadeh Joshua A Salomon Evanson Zondani Sambala Abdallah M Samy Milena M Santric Milicevic Bruno Piassi Sao Jose Sivan Yegnanarayana Iyer Saraswathy Rodrigo Sarmiento-Suárez Benn Sartorius Brijesh Sathian Sonia Saxena Alyssa N Sbarra Lauren E Schaeffer David C Schwebel Sadaf G Sepanlou Seyedmojtaba Seyedmousavi Faramarz Shaahmadi Masood Ali Shaikh Mehran Shams-Beyranvand Amir Shamshirian Morteza Shamsizadeh Kiomars Sharafi Mehdi Sharif Mahdi Sharif-Alhoseini Hamid Sharifi Jayendra Sharma Rajesh Sharma Aziz Sheikh Chloe Shields Mika Shigematsu Rahman Shiri Ivy Shiue Kerem Shuval Tariq J Siddiqi João Pedro Silva Jasvinder A Singh Dhirendra Narain Sinha Malede Mequanent Sisay Solomon Sisay Karen Sliwa David L Smith Ranjani Somayaji Moslem Soofi Joan B Soriano Chandrashekhar T Sreeramareddy Agus Sudaryanto Mu'awiyyah Babale Sufiyan Bryan L Sykes P N Sylaja Rafael Tabarés-Seisdedos Karen M Tabb Takahiro Tabuchi Nuno Taveira Mohamad-Hani Temsah Abdullah Sulieman Terkawi Zemenu Tadesse Tessema Kavumpurathu Raman Thankappan Sathish Thirunavukkarasu Quyen G To Marcos Roberto Tovani-Palone Bach Xuan Tran Khanh Bao Tran Irfan Ullah Muhammad Shariq Usman Olalekan A Uthman Amir Vahedian-Azimi Pascual R Valdez Job F M van Boven Tommi Juhani Vasankari Yasser Vasseghian Yousef Veisani Narayanaswamy Venketasubramanian Francesco S Violante Sergey Konstantinovitch Vladimirov Vasily Vlassov Theo Vos Giang Thu Vu Isidora S Vujcic Yasir Waheed Jon Wakefield Haidong Wang Yafeng Wang Yuan-Pang Wang Joseph L Ward Robert G Weintraub Kidu Gidey Weldegwergs Girmay Teklay Weldesamuel Ronny Westerman Charles Shey Wiysonge Dawit Zewdu Wondafrash Lauren Woyczynski Ai-Min Wu Gelin Xu Abbas Yadegar Tomohide Yamada Vahid Yazdi-Feyzabadi Christopher Sabo Yilgwan Paul Yip Naohiro Yonemoto Javad Yoosefi Lebni Mustafa Z Younis Mahmoud Yousefifard Hebat-Allah Salah A Yousof Chuanhua Yu Hasan Yusefzadeh Erfan Zabeh Telma Zahirian Moghadam Sojib Bin Zaman Mohammad Zamani Hamed Zandian Alireza Zangeneh Taddese Alemu Zerfu Yunquan Zhang Arash Ziapour Sanjay Zodpey Christopher J L Murray Simon I Hay

Nature 2019 10 16;574(7778):353-358. Epub 2019 Oct 16.

Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA, USA.

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2-to end preventable child deaths by 2030-we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000-2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations.
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http://dx.doi.org/10.1038/s41586-019-1545-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800389PMC
October 2019

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study.

Authors:
Christina Fitzmaurice Degu Abate Naghmeh Abbasi Hedayat Abbastabar Foad Abd-Allah Omar Abdel-Rahman Ahmed Abdelalim Amir Abdoli Ibrahim Abdollahpour Abdishakur S M Abdulle Nebiyu Dereje Abebe Haftom Niguse Abraha Laith Jamal Abu-Raddad Ahmed Abualhasan Isaac Akinkunmi Adedeji Shailesh M Advani Mohsen Afarideh Mahdi Afshari Mohammad Aghaali Dominic Agius Sutapa Agrawal Ayat Ahmadi Elham Ahmadian Ehsan Ahmadpour Muktar Beshir Ahmed Mohammad Esmaeil Akbari Tomi Akinyemiju Ziyad Al-Aly Assim M AlAbdulKader Fares Alahdab Tahiya Alam Genet Melak Alamene Birhan Tamene T Alemnew Kefyalew Addis Alene Cyrus Alinia Vahid Alipour Syed Mohamed Aljunid Fatemeh Allah Bakeshei Majid Abdulrahman Hamad Almadi Amir Almasi-Hashiani Ubai Alsharif Shirina Alsowaidi Nelson Alvis-Guzman Erfan Amini Saeed Amini Yaw Ampem Amoako Zohreh Anbari Nahla Hamed Anber Catalina Liliana Andrei Mina Anjomshoa Fereshteh Ansari Ansariadi Ansariadi Seth Christopher Yaw Appiah Morteza Arab-Zozani Jalal Arabloo Zohreh Arefi Olatunde Aremu Habtamu Abera Areri Al Artaman Hamid Asayesh Ephrem Tsegay Asfaw Alebachew Fasil Ashagre Reza Assadi Bahar Ataeinia Hagos Tasew Atalay Zerihun Ataro Suleman Atique Marcel Ausloos Leticia Avila-Burgos Euripide F G A Avokpaho Ashish Awasthi Nefsu Awoke Beatriz Paulina Ayala Quintanilla Martin Amogre Ayanore Henok Tadesse Ayele Ebrahim Babaee Umar Bacha Alaa Badawi Mojtaba Bagherzadeh Eleni Bagli Senthilkumar Balakrishnan Abbas Balouchi Till Winfried Bärnighausen Robert J Battista Masoud Behzadifar Meysam Behzadifar Bayu Begashaw Bekele Yared Belete Belay Yaschilal Muche Belayneh Kathleen Kim Sachiko Berfield Adugnaw Berhane Eduardo Bernabe Mircea Beuran Nickhill Bhakta Krittika Bhattacharyya Belete Biadgo Ali Bijani Muhammad Shahdaat Bin Sayeed Charles Birungi Catherine Bisignano Helen Bitew Tone Bjørge Archie Bleyer Kassawmar Angaw Bogale Hunduma Amensisa Bojia Antonio M Borzì Cristina Bosetti Ibrahim R Bou-Orm Hermann Brenner Jerry D Brewer Andrey Nikolaevich Briko Nikolay Ivanovich Briko Maria Teresa Bustamante-Teixeira Zahid A Butt Giulia Carreras Juan J Carrero Félix Carvalho Clara Castro Franz Castro Ferrán Catalá-López Ester Cerin Yazan Chaiah Wagaye Fentahun Chanie Vijay Kumar Chattu Pankaj Chaturvedi Neelima Singh Chauhan Mohammad Chehrazi Peggy Pei-Chia Chiang Tesfaye Yitna Chichiabellu Onyema Greg Chido-Amajuoyi Odgerel Chimed-Ochir Jee-Young J Choi Devasahayam J Christopher Dinh-Toi Chu Maria-Magdalena Constantin Vera M Costa Emanuele Crocetti Christopher Stephen Crowe Maria Paula Curado Saad M A Dahlawi Giovanni Damiani Amira Hamed Darwish Ahmad Daryani José das Neves Feleke Mekonnen Demeke Asmamaw Bizuneh Demis Birhanu Wondimeneh Demissie Gebre Teklemariam Demoz Edgar Denova-Gutiérrez Afshin Derakhshani Kalkidan Solomon Deribe Rupak Desai Beruk Berhanu Desalegn Melaku Desta Subhojit Dey Samath Dhamminda Dharmaratne Meghnath Dhimal Daniel Diaz Mesfin Tadese Tadese Dinberu Shirin Djalalinia David Teye Doku Thomas M Drake Manisha Dubey Eleonora Dubljanin Eyasu Ejeta Duken Hedyeh Ebrahimi Andem Effiong Aziz Eftekhari Iman El Sayed Maysaa El Sayed Zaki Shaimaa I El-Jaafary Ziad El-Khatib Demelash Abewa Elemineh Hajer Elkout Richard G Ellenbogen Aisha Elsharkawy Mohammad Hassan Emamian Daniel Adane Endalew Aman Yesuf Endries Babak Eshrati Ibtihal Fadhil Vahid Fallah Omrani Mahbobeh Faramarzi Mahdieh Abbasalizad Farhangi Andrea Farioli Farshad Farzadfar Netsanet Fentahun Eduarda Fernandes Garumma Tolu Feyissa Irina Filip Florian Fischer James L Fisher Lisa M Force Masoud Foroutan Marisa Freitas Takeshi Fukumoto Neal D Futran Silvano Gallus Fortune Gbetoho Gankpe Reta Tsegaye Gayesa Tsegaye Tewelde Gebrehiwot Gebreamlak Gebremedhn Gebremeskel Getnet Azeze Gedefaw Belayneh K Gelaw Birhanu Geta Sefonias Getachew Kebede Embaye Gezae Mansour Ghafourifard Alireza Ghajar Ahmad Ghashghaee Asadollah Gholamian Paramjit Singh Gill Themba T G Ginindza Alem Girmay Muluken Gizaw Ricardo Santiago Gomez Sameer Vali Gopalani Giuseppe Gorini Bárbara Niegia Garcia Goulart Ayman Grada Maximiliano Ribeiro Guerra Andre Luiz Sena Guimaraes Prakash C Gupta Rahul Gupta Kishor Hadkhale Arvin Haj-Mirzaian Arya Haj-Mirzaian Randah R Hamadeh Samer Hamidi Lolemo Kelbiso Hanfore Josep Maria Haro Milad Hasankhani Amir Hasanzadeh Hamid Yimam Hassen Roderick J Hay Simon I Hay Andualem Henok Nathaniel J Henry Claudiu Herteliu Hagos D Hidru Chi Linh Hoang Michael K Hole Praveen Hoogar Nobuyuki Horita H Dean Hosgood Mostafa Hosseini Mehdi Hosseinzadeh Mihaela Hostiuc Sorin Hostiuc Mowafa Househ Mohammedaman Mama Hussen Bogdan Ileanu Milena D Ilic Kaire Innos Seyed Sina Naghibi Irvani Kufre Robert Iseh Sheikh Mohammed Shariful Islam Farhad Islami Nader Jafari Balalami Morteza Jafarinia Leila Jahangiry Mohammad Ali Jahani Nader Jahanmehr Mihajlo Jakovljevic Spencer L James Mehdi Javanbakht Sudha Jayaraman Sun Ha Jee Ensiyeh Jenabi Ravi Prakash Jha Jost B Jonas Jitendra Jonnagaddala Tamas Joo Suresh Banayya Jungari Mikk Jürisson Ali Kabir Farin Kamangar André Karch Narges Karimi Ansar Karimian Amir Kasaeian Gebremicheal Gebreslassie Kasahun Belete Kassa Tesfaye Dessale Kassa Mesfin Wudu Kassaw Anil Kaul Peter Njenga Keiyoro Abraham Getachew Kelbore Amene Abebe Kerbo Yousef Saleh Khader Maryam Khalilarjmandi Ejaz Ahmad Khan Gulfaraz Khan Young-Ho Khang Khaled Khatab Amir Khater Maryam Khayamzadeh Maryam Khazaee-Pool Salman Khazaei Abdullah T Khoja Mohammad Hossein Khosravi Jagdish Khubchandani Neda Kianipour Daniel Kim Yun Jin Kim Adnan Kisa Sezer Kisa Katarzyna Kissimova-Skarbek Hamidreza Komaki Ai Koyanagi Kristopher J Krohn Burcu Kucuk Bicer Nuworza Kugbey Vivek Kumar Desmond Kuupiel Carlo La Vecchia Deepesh P Lad Eyasu Alem Lake Ayenew Molla Lakew Dharmesh Kumar Lal Faris Hasan Lami Qing Lan Savita Lasrado Paolo Lauriola Jeffrey V Lazarus James Leigh Cheru Tesema Leshargie Yu Liao Miteku Andualem Limenih Stefan Listl Alan D Lopez Platon D Lopukhov Raimundas Lunevicius Mohammed Madadin Sameh Magdeldin Hassan Magdy Abd El Razek Azeem Majeed Afshin Maleki Reza Malekzadeh Ali Manafi Navid Manafi Wondimu Ayele Manamo Morteza Mansourian Mohammad Ali Mansournia Lorenzo Giovanni Mantovani Saman Maroufizadeh Santi Martini S Martini Tivani Phosa Mashamba-Thompson Benjamin Ballard Massenburg Motswadi Titus Maswabi Manu Raj Mathur Colm McAlinden Martin McKee Hailemariam Abiy Alemu Meheretu Ravi Mehrotra Varshil Mehta Toni Meier Yohannes A Melaku Gebrekiros Gebremichael Meles Hagazi Gebre Meles Addisu Melese Mulugeta Melku Peter T N Memiah Walter Mendoza Ritesh G Menezes Shahin Merat Tuomo J Meretoja Tomislav Mestrovic Bartosz Miazgowski Tomasz Miazgowski Kebadnew Mulatu M Mihretie Ted R Miller Edward J Mills Seyed Mostafa Mir Hamed Mirzaei Hamid Reza Mirzaei Rashmi Mishra Babak Moazen Dara K Mohammad Karzan Abdulmuhsin Mohammad Yousef Mohammad Aso Mohammad Darwesh Abolfazl Mohammadbeigi Hiwa Mohammadi Moslem Mohammadi Mahdi Mohammadian Abdollah Mohammadian-Hafshejani Milad Mohammadoo-Khorasani Reza Mohammadpourhodki Ammas Siraj Mohammed Jemal Abdu Mohammed Shafiu Mohammed Farnam Mohebi Ali H Mokdad Lorenzo Monasta Yoshan Moodley Mahmood Moosazadeh Maryam Moossavi Ghobad Moradi Mohammad Moradi-Joo Maziar Moradi-Lakeh Farhad Moradpour Lidia Morawska Joana Morgado-da-Costa Naho Morisaki Shane Douglas Morrison Abbas Mosapour Seyyed Meysam Mousavi Achenef Asmamaw Muche Oumer Sada S Muhammed Jonah Musa Ashraf F Nabhan Mehdi Naderi Ahamarshan Jayaraman Nagarajan Gabriele Nagel Azin Nahvijou Gurudatta Naik Farid Najafi Luigi Naldi Hae Sung Nam Naser Nasiri Javad Nazari Ionut Negoi Subas Neupane Polly A Newcomb Haruna Asura Nggada Josephine W Ngunjiri Cuong Tat Nguyen Leila Nikniaz Dina Nur Anggraini Ningrum Yirga Legesse Nirayo Molly R Nixon Chukwudi A Nnaji Marzieh Nojomi Shirin Nosratnejad Malihe Nourollahpour Shiadeh Mohammed Suleiman Obsa Richard Ofori-Asenso Felix Akpojene Ogbo In-Hwan Oh Andrew T Olagunju Tinuke O Olagunju Mojisola Morenike Oluwasanu Abidemi E Omonisi Obinna E Onwujekwe Anu Mary Oommen Eyal Oren Doris D V Ortega-Altamirano Erika Ota Stanislav S Otstavnov Mayowa Ojo Owolabi Mahesh P A Jagadish Rao Padubidri Smita Pakhale Amir H Pakpour Adrian Pana Eun-Kee Park Hadi Parsian Tahereh Pashaei Shanti Patel Snehal T Patil Alyssa Pennini David M Pereira Cristiano Piccinelli Julian David Pillay Majid Pirestani Farhad Pishgar Maarten J Postma Hadi Pourjafar Farshad Pourmalek Akram Pourshams Swayam Prakash Narayan Prasad Mostafa Qorbani Mohammad Rabiee Navid Rabiee Amir Radfar Alireza Rafiei Fakher Rahim Mahdi Rahimi Muhammad Aziz Rahman Fatemeh Rajati Saleem M Rana Samira Raoofi Goura Kishor Rath David Laith Rawaf Salman Rawaf Robert C Reiner Andre M N Renzaho Nima Rezaei Aziz Rezapour Ana Isabel Ribeiro Daniela Ribeiro Luca Ronfani Elias Merdassa Roro Gholamreza Roshandel Ali Rostami Ragy Safwat Saad Parisa Sabbagh Siamak Sabour Basema Saddik Saeid Safiri Amirhossein Sahebkar Mohammad Reza Salahshoor Farkhonde Salehi Hosni Salem Marwa Rashad Salem Hamideh Salimzadeh Joshua A Salomon Abdallah M Samy Juan Sanabria Milena M Santric Milicevic Benn Sartorius Arash Sarveazad Brijesh Sathian Maheswar Satpathy Miloje Savic Monika Sawhney Mehdi Sayyah Ione J C Schneider Ben Schöttker Mario Sekerija Sadaf G Sepanlou Masood Sepehrimanesh Seyedmojtaba Seyedmousavi Faramarz Shaahmadi Hosein Shabaninejad Mohammad Shahbaz Masood Ali Shaikh Amir Shamshirian Morteza Shamsizadeh Heidar Sharafi Zeinab Sharafi Mehdi Sharif Ali Sharifi Hamid Sharifi Rajesh Sharma Aziz Sheikh Reza Shirkoohi Sharvari Rahul Shukla Si Si Soraya Siabani Diego Augusto Santos Silva Dayane Gabriele Alves Silveira Ambrish Singh Jasvinder A Singh Solomon Sisay Freddy Sitas Eugène Sobngwi Moslem Soofi Joan B Soriano Vasiliki Stathopoulou Mu'awiyyah Babale Sufiyan Rafael Tabarés-Seisdedos Takahiro Tabuchi Ken Takahashi Omid Reza Tamtaji Mohammed Rasoul Tarawneh Segen Gebremeskel Tassew Parvaneh Taymoori Arash Tehrani-Banihashemi Mohamad-Hani Temsah Omar Temsah Berhe Etsay Tesfay Fisaha Haile Tesfay Manaye Yihune Teshale Gizachew Assefa Tessema Subash Thapa Kenean Getaneh Tlaye Roman Topor-Madry Marcos Roberto Tovani-Palone Eugenio Traini Bach Xuan Tran Khanh Bao Tran Afewerki Gebremeskel Tsadik Irfan Ullah Olalekan A Uthman Marco Vacante Maryam Vaezi Patricia Varona Pérez Yousef Veisani Simone Vidale Francesco S Violante Vasily Vlassov Stein Emil Vollset Theo Vos Kia Vosoughi Giang Thu Vu Isidora S Vujcic Henry Wabinga Tesfahun Mulatu Wachamo Fasil Shiferaw Wagnew Yasir Waheed Fitsum Weldegebreal Girmay Teklay Weldesamuel Tissa Wijeratne Dawit Zewdu Wondafrash Tewodros Eshete Wonde Adam Belay Wondmieneh Hailemariam Mekonnen Workie Rajaram Yadav Abbas Yadegar Ali Yadollahpour Mehdi Yaseri Vahid Yazdi-Feyzabadi Alex Yeshaneh Mohammed Ahmed Yimam Ebrahim M Yimer Engida Yisma Naohiro Yonemoto Mustafa Z Younis Bahman Yousefi Mahmoud Yousefifard Chuanhua Yu Erfan Zabeh Vesna Zadnik Telma Zahirian Moghadam Zoubida Zaidi Mohammad Zamani Hamed Zandian Alireza Zangeneh Leila Zaki Kazem Zendehdel Zerihun Menlkalew Zenebe Taye Abuhay Zewale Arash Ziapour Sanjay Zodpey Christopher J L Murray

JAMA Oncol 2019 12;5(12):1749-1768

Institute for Health Metrics and Evaluation, University of Washington, Seattle.

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data.

Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning.

Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence.

Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs).

Conclusions And Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.
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http://dx.doi.org/10.1001/jamaoncol.2019.2996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777271PMC
December 2019

Translocation-generated ITK-FER and ITK-SYK fusions induce STAT3 phosphorylation and CD69 expression.

Biochem Biophys Res Commun 2018 10 11;504(4):749-752. Epub 2018 Sep 11.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86, Huddinge, Sweden. Electronic address:

Many cancer types carry mutations in protein tyrosine kinase (PTK) and such alterations frequently drive tumor progression. One category is gene translocation of PTKs yielding chimeric proteins with transforming capacity. In this study, we characterized the role of ITK-FER [Interleukin-2-inducible T-cell Kinase (ITK) gene fused with Feline Encephalitis Virus-Related kinase (FER) gene] and ITK-SYK [Interleukin-2-inducible T-cell Kinase (ITK) gene fused with the Spleen Tyrosine Kinase (SYK)] in Peripheral T Cell Lymphoma (PTCL) signaling. We observed an induction of tyrosine phosphorylation events in the presence of both ITK-FER and ITK-SYK. The downstream targets of ITK-FER and ITK-SYK were explored and STAT3 was found to be highly phosphorylated by these fusion kinases. In addition, the CD69 T-cell activation marker was significantly elevated. Apart from tyrosine kinase inhibitors acting directly on the fusions, we believe that drugs acting on downstream targets could serve as alternative cancer therapies for fusion PTKs.
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http://dx.doi.org/10.1016/j.bbrc.2018.09.019DOI Listing
October 2018

Systematic Methodological Evaluation of a Multiplex Bead-Based Flow Cytometry Assay for Detection of Extracellular Vesicle Surface Signatures.

Front Immunol 2018 13;9:1326. Epub 2018 Jun 13.

Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Extracellular vesicles (EVs) can be harvested from cell culture supernatants and from all body fluids. EVs can be conceptually classified based on their size and biogenesis as exosomes and microvesicles. Nowadays, it is however commonly accepted in the field that there is a much higher degree of heterogeneity within these two subgroups than previously thought. For instance, the surface marker profile of EVs is likely dependent on the cell source, the cell's activation status, and multiple other parameters. Within recent years, several new methods and assays to study EV heterogeneity in terms of surface markers have been described; most of them are being based on flow cytometry. Unfortunately, such methods generally require dedicated instrumentation, are time-consuming and demand extensive operator expertise for sample preparation, acquisition, and data analysis. In this study, we have systematically evaluated and explored the use of a multiplex bead-based flow cytometric assay which is compatible with most standard flow cytometers and facilitates a robust semi-quantitative detection of 37 different potential EV surface markers in one sample simultaneously. First, assay variability, sample stability over time, and dynamic range were assessed together with the limitations of this assay in terms of EV input quantity required for detection of differently abundant surface markers. Next, the potential effects of EV origin, sample preparation, and quality of the EV sample on the assay were evaluated. The findings indicate that this multiplex bead-based assay is generally suitable to detect, quantify, and compare EV surface signatures in various sample types, including unprocessed cell culture supernatants, cell culture-derived EVs isolated by different methods, and biological fluids. Furthermore, the use and limitations of this assay to assess heterogeneities in EV surface signatures was explored by combining different sets of detection antibodies in EV samples derived from different cell lines and subsets of rare cells. Taken together, this validated multiplex bead-based flow cytometric assay allows robust, sensitive, and reproducible detection of EV surface marker expression in various sample types in a semi-quantitative way and will be highly valuable for many researchers in the EV field in different experimental contexts.
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http://dx.doi.org/10.3389/fimmu.2018.01326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008374PMC
June 2018

Terminating B cell receptor signaling.

Oncotarget 2017 Dec 6;8(66):109857-109858. Epub 2017 Dec 6.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Stockholm, Sweden.

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http://dx.doi.org/10.18632/oncotarget.22986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746347PMC
December 2017

ANKRD54 preferentially selects Bruton's Tyrosine Kinase (BTK) from a Human Src-Homology 3 (SH3) domain library.

PLoS One 2017 3;12(4):e0174909. Epub 2017 Apr 3.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, SE Stockholm, Sweden.

Bruton's Tyrosine Kinase (BTK) is a cytoplasmic protein tyrosine kinase with a fundamental role in B-lymphocyte development and activation. The nucleocytoplasmic shuttling of BTK is specifically modulated by the Ankyrin Repeat Domain 54 (ANKRD54) protein and the interaction is known to be exclusively SH3-dependent. To identify the spectrum of the ANKRD54 SH3-interactome, we applied phage-display screening of a library containing all the 296 human SH3 domains. The BTK-SH3 domain was the prime interactor. Quantitative western blotting analysis demonstrated the accuracy of the screening procedure. Revealing the spectrum and specificity of ANKRD54-interactome is a critical step toward functional analysis in cells and tissues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174909PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378395PMC
September 2017

B Cell Receptor Activation Predominantly Regulates AKT-mTORC1/2 Substrates Functionally Related to RNA Processing.

PLoS One 2016 3;11(8):e0160255. Epub 2016 Aug 3.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska Hospital Huddinge, SE-141 86 Huddinge-Stockholm, Sweden.

Protein kinase B (AKT) phosphorylates numerous substrates on the consensus motif RXRXXpS/T, a docking site for 14-3-3 interactions. To identify novel AKT-induced phosphorylation events following B cell receptor (BCR) activation, we performed proteomics, biochemical and bioinformatics analyses. Phosphorylated consensus motif-specific antibody enrichment, followed by tandem mass spectrometry, identified 446 proteins, containing 186 novel phosphorylation events. Moreover, we found 85 proteins with up regulated phosphorylation, while in 277 it was down regulated following stimulation. Up regulation was mainly in proteins involved in ribosomal and translational regulation, DNA binding and transcription regulation. Conversely, down regulation was preferentially in RNA binding, mRNA splicing and mRNP export proteins. Immunoblotting of two identified RNA regulatory proteins, RBM25 and MEF-2D, confirmed the proteomics data. Consistent with these findings, the AKT-inhibitor (MK-2206) dramatically reduced, while the mTORC-inhibitor PP242 totally blocked phosphorylation on the RXRXXpS/T motif. This demonstrates that this motif, previously suggested as an AKT target sequence, also is a substrate for mTORC1/2. Proteins with PDZ, PH and/or SH3 domains contained the consensus motif, whereas in those with an HMG-box, H15 domains and/or NF-X1-zinc-fingers, the motif was absent. Proteins carrying the consensus motif were found in all eukaryotic clades indicating that they regulate a phylogenetically conserved set of proteins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160255PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972398PMC
August 2017

Protein kinase B (AKT) regulates SYK activity and shuttling through 14-3-3 and importin 7.

Int J Biochem Cell Biol 2016 09 2;78:63-74. Epub 2016 Jul 2.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska Hospital Huddinge, SE-141 86 Huddinge, Stockholm, Sweden. Electronic address:

The Protein kinase B (AKT) regulates a plethora of intracellular signaling proteins to fine-tune signaling of multiple pathways. Here, we found that following B-cell receptor (BCR)-induced tyrosine phosphorylation of the cytoplasmic tyrosine kinase SYK and the adaptor BLNK, the AKT/PKB enzyme strongly induced BLNK (>100-fold) and SYK (>100-fold) serine/threonine phosphorylation (pS/pT). Increased phosphorylation promoted 14-3-3 binding to BLNK (37-fold) and SYK (2.5-fold) in a pS/pT-concentration dependent manner. We also demonstrated that the AKT inhibitor MK2206 reduced pS/pT of both BLNK (3-fold) and SYK (2.5-fold). Notably, the AKT phosphatase, PHLPP2 maintained the activating phosphorylation of BLNK at Y84 and increased protein stability (8.5-fold). In addition, 14-3-3 was required for the regulation SYK's interaction with BLNK and attenuated SYK binding to Importin 7 (5-fold), thereby perturbing shuttling to the nucleus. Moreover, 14-3-3 proteins also sustained tyrosine phosphorylation of SYK and BLNK. Furthermore, substitution of S295 or S297 for alanine abrogated SYK's binding to Importin 7. SYK with S295A or S297A replacements showed intense pY525/526 phosphorylation, and BLNK pY84 phosphorylation correlated with the SYK pY525/526 phosphorylation level. Conversely, the corresponding mutations to aspartic acid in SYK reduced pY525/526 phosphorylation. Collectively, these and previous results suggest that AKT and 14-3-3 proteins down-regulate the activity of several BCR-associated components, including BTK, BLNK and SYK and also inhibit SYK's interaction with Importin 7.
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http://dx.doi.org/10.1016/j.biocel.2016.06.024DOI Listing
September 2016

Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells.

Br J Haematol 2016 07 15;174(1):117-26. Epub 2016 Mar 15.

Haematology Centre and Centre for Haematology and Regenerative Medicine (HERM), Karolinska University Hospital, Stockholm, Sweden.

The small molecule APR-246 (PRIMA-1(MET) ) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off-target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up-regulated. APR-246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up-regulated by APR-246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1. Up-regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up-regulation and nuclear translocation by APR-246. Down-regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR-246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR-246-induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR-246, resulting in synergistic cell killing together with APR-246. In conclusion, ROS induction is important for antileukaemic activities of APR-246 and inhibiting the protective response of the Nrf-2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.
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http://dx.doi.org/10.1111/bjh.14036DOI Listing
July 2016

Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model.

J Clin Invest 2014 Sep 8;124(9):4067-81. Epub 2014 Aug 8.

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
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http://dx.doi.org/10.1172/JCI76175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151202PMC
September 2014

Dual phosphorylation of Btk by Akt/protein kinase b provides docking for 14-3-3ζ, regulates shuttling, and attenuates both tonic and induced signaling in B cells.

Mol Cell Biol 2013 Aug 10;33(16):3214-26. Epub 2013 Jun 10.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska Hospital Huddinge, Huddinge, Stockholm, Sweden.

Bruton's tyrosine kinase (Btk) is crucial for B-lymphocyte activation and development. Mutations in the Btk gene cause X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Using tandem mass spectrometry, 14-3-3ζ was identified as a new binding partner and negative regulator of Btk in both B-cell lines and primary B lymphocytes. The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain. The double-alanine, S51A/T495A, replacement mutant failed to bind 14-3-3ζ, while phosphomimetic aspartate substitutions, S51D/T495D, caused enhanced interaction. The phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY294002 abrogated S51/T495 phosphorylation and binding. A newly characterized 14-3-3 inhibitor, BV02, reduced binding, as did the Btk inhibitor PCI-32765 (ibrutinib). Interestingly, in the presence of BV02, phosphorylation of Btk, phospholipase Cγ2, and NF-κB increased strongly, suggesting that 14-3-3 also regulates B-cell receptor (BCR)-mediated tonic signaling. Furthermore, downregulation of 14-3-3ζ elevated nuclear translocation of Btk. The loss-of-function mutant S51A/T495A showed reduced tyrosine phosphorylation and ubiquitination. Conversely, the gain-of-function mutant S51D/T495D exhibited intense tyrosine phosphorylation, associated with Btk ubiquitination and degradation, likely contributing to the termination of BCR signaling. Collectively, this suggests that Btk could become an important new candidate for the general study of 14-3-3-mediated regulation.
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http://dx.doi.org/10.1128/MCB.00247-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753922PMC
August 2013

Signaling of the ITK (interleukin 2-inducible T cell kinase)-SYK (spleen tyrosine kinase) fusion kinase is dependent on adapter SLP-76 and on the adapter function of the kinases SYK and ZAP70.

J Biol Chem 2013 Mar 4;288(10):7338-50. Epub 2013 Jan 4.

Department of Laboratory Medicine, Karolinska Institutet, Karolinska Hospital, Huddinge, SE 141 86 Stockholm, Sweden.

The inducible T cell kinase-spleen tyrosine kinase (ITK-SYK) oncogene consists of the Tec homology-pleckstrin homology domain of ITK and the kinase domain of SYK, and it is believed to be the cause of peripheral T cell lymphoma. We and others have recently demonstrated that this fusion protein is constitutively tyrosine-phosphorylated and is transforming both in vitro and in vivo. To gain a deeper insight into the molecular mechanism(s) underlying its activation and signaling, we mutated a total of eight tyrosines located in the SYK portion of the chimera into either phenylalanine or to the negatively charged glutamic acid. Although mutations in the interdomain-B region affected ITK-SYK kinase activity, they only modestly altered downstream signaling events. In contrast, mutations that were introduced in the kinase domain triggered severe impairment of downstream signaling. Moreover, we show here that SLP-76 is critical for ITK-SYK activation and is particularly required for the ITK-SYK-dependent phosphorylation of SYK activation loop tyrosines. In Jurkat cell lines, we demonstrate that expression of ITK-SYK fusion requires an intact SLP-76 function and significantly induces IL-2 secretion and CD69 expression. Furthermore, the SLP-76-mediated induction of IL-2 and CD69 could be further enhanced by SYK or ZAP-70, but it was independent of their kinase activity. Notably, ITK-SYK expression in SYF cells phosphorylates SLP-76 in the absence of SRC family kinases. Altogether, our data suggest that ITK-SYK exists in the active conformation state and is therefore capable of signaling without SRC family kinases or stimulation of the T cell receptor.
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http://dx.doi.org/10.1074/jbc.M112.374967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591642PMC
March 2013

Regulation of nucleocytoplasmic shuttling of Bruton's tyrosine kinase (Btk) through a novel SH3-dependent interaction with ankyrin repeat domain 54 (ANKRD54).

Mol Cell Biol 2012 Jul 23;32(13):2440-53. Epub 2012 Apr 23.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.

Bruton's tyrosine kinase (Btk), belonging to the Tec family of tyrosine kinases (TFKs), is essential for B-lymphocyte development. Abrogation of Btk signaling causes human X-linked agammaglobulinemia (XLA) and murine X-linked immunodeficiency (Xid). We employed affinity purification of Flag-tagged Btk, combined with tandem mass spectrometry, to capture and identify novel interacting proteins. We here characterize the interaction with ankryin repeat domain 54 protein (ANKRD54), also known as Lyn-interacting ankyrin repeat protein (Liar). While Btk is a nucleocytoplasmic protein, the Liar pool was found to shuttle at a higher rate than Btk. Importantly, our results suggest that Liar mediates nuclear export of both Btk and another TFK, Txk/Rlk. Liar-mediated Btk shuttling was enriched for activation loop, nonphosphorylated Btk and entirely dependent on Btk's SH3 domain. Liar also showed reduced binding to an aspartic acid phosphomimetic SH3 mutant. Three other investigated nucleus-located proteins, Abl, estrogen receptor β (ERβ), and transcription factor T-bet, were all unaffected by Liar. We mapped the interaction site to the C terminus of the Btk SH3 domain. A biotinylated, synthetic Btk peptide, ARDKNGQEGYIPSNYVTEAEDS, was sufficient for this interaction. Liar is the first protein identified that specifically influences the nucleocytoplasmic shuttling of Btk and Txk and belongs to a rare group of known proteins carrying out this activity in a Crm1-dependent manner.
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http://dx.doi.org/10.1128/MCB.06620-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434478PMC
July 2012

TEC family kinases in health and disease--loss-of-function of BTK and ITK and the gain-of-function fusions ITK-SYK and BTK-SYK.

FEBS J 2011 Jun 18;278(12):2001-10. Epub 2011 May 18.

Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Huddinge University Hospital, Sweden.

The TEC family is ancient and constitutes the second largest family of cytoplasmic tyrosine kinases. In 1993, loss-of-function mutations in the BTK gene were reported as the cause of X-linked agammaglobulinemia. Of all the existing 90 tyrosine kinases in humans, Bruton's tyrosine kinase (BTK) is the kinase for which most mutations have been identified. These experiments of nature collectively provide a form of mutation scanning with direct implications for the several hundred endogenous signaling proteins carrying domains also found in BTK. In 2009, an inactivating mutation in the ITK gene was shown to cause susceptibility to lethal Epstein-Barr virus infection. Both kinases represent interesting targets for inhibition: in the case of BTK, as an immunosuppressant, whereas there is evidence that the inhibition of inducible T-cell kinase (ITK) could influence the infectivity of HIV and also have anti-inflammatory activity. Since 2006, several patients carrying a fusion protein, originating from a translocation joining genes encoding the kinases ITK and spleen tyrosine kinase (SYK), have been shown to develop T-cell lymphoma. We review these disease processes and also describe the role of the N-terminal pleckstrin homology-Tec homology (PH-TH) domain doublet of BTK and ITK in the downstream intracellular signaling of such fusion proteins.
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http://dx.doi.org/10.1111/j.1742-4658.2011.08134.xDOI Listing
June 2011