Abstract:
:Merkel cell polyomavirus (MCV) causes ~80% of primary and metastatic Merkel cell carcinomas (MCCs). By comparing digital transcriptome subtraction deep-sequencing profiles, we found that transcripts of the cellular survivin oncoprotein [BIRC5a (baculoviral inhibitor of apoptosis repeat-containing 5)] were up-regulated sevenfold in virus-positive compared to virus-negative MCC tumors. Knockdown of MCV large T antigen in MCV-positive MCC cell lines decreased survivin mRNA and protein expression. Exogenously expressed MCV large T antigen increased survivin protein expression in non-MCC primary cells. This required an intact retinoblastoma protein-targeting domain that activated survivin gene transcription as well as expression of other G(1)-S-phase proteins including E2F1 and cyclin E. Survivin expression is critical to the survival of MCV-positive MCC cells. A small-molecule survivin inhibitor, YM155, potently and selectively initiates irreversible, nonapoptotic, programmed MCV-positive MCC cell death. Of 1360 other chemotherapeutic and pharmacologically active compounds screened in vitro, only bortezomib (Velcade) was found to be similarly potent, but was not selective in killing MCV-positive MCC cells. YM155 halted the growth of MCV-positive MCC xenograft tumors and was nontoxic in mice, whereas bortezomib was not active in vivo and mice displayed serious morbidity. Xenograft tumors resumed growth once YM155 treatment was stopped, suggesting that YM155 may be cytostatic rather than cytotoxic in vivo. Identifying the cellular pathways, such as those involving survivin, that are targeted by tumor viruses can lead to rapid and rational identification of drug candidates for treating virus-induced cancers.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Arora R,Shuda M,Guastafierro A,Feng H,Toptan T,Tolstov Y,Normolle D,Vollmer LL,Vogt A,Dömling A,Brodsky JL,Chang Y,Moore PSdoi
10.1126/scitranslmed.3003713subject
Has Abstractpub_date
2012-05-09 00:00:00pages
133ra56issue
133eissn
1946-6234issn
1946-6242pii
4/133/133ra56journal_volume
4pub_type
杂志文章abstract::A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aai7514
更新日期:2017-03-15 00:00:00
abstract::Rapid antimicrobial susceptibility testing (AST) is urgently needed for informing treatment decisions and preventing the spread of antimicrobial resistance resulting from the misuse and overuse of antibiotics. To date, no phenotypic AST exists that can be performed within a single patient visit (30 min) directly from ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aal3693
更新日期:2017-10-04 00:00:00
abstract::Advances in understanding the genetics and underlying pathology of the catastrophic childhood epilepsies are pointing toward treatments. ...
journal_title:Science translational medicine
pub_type:
doi:10.1126/scitranslmed.3010531
更新日期:2014-11-12 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated wi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aad9157
更新日期:2017-05-03 00:00:00
abstract::Clinical advancement of the bioartificial liver is hampered by the lack of expandable human hepatocytes and appropriate bioreactors and carriers to encourage hepatic cells to function during extracorporeal circulation. We have recently developed an efficient approach for derivation of expandable liver progenitor-like ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aba5146
更新日期:2020-07-08 00:00:00
abstract::A set of principles is proposed for sponsors and developers of research computing applications that can increase the likelihood of successful adoption by researchers. ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3004032
更新日期:2012-08-29 00:00:00
abstract::Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K-nul...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw6143
更新日期:2020-02-05 00:00:00
abstract::Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detail...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aas9668
更新日期:2018-08-22 00:00:00
abstract::Systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) of the skin are autoimmune diseases characterized by inappropriate immune responses against self-proteins; the key elements that determine disease pathogenesis and progression are largely unknown. Here, we show that mice lacking immune inhibitory...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aax1159
更新日期:2019-12-11 00:00:00
abstract::Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents whil...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3009951
更新日期:2015-02-04 00:00:00
abstract::In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthrit...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aah3438
更新日期:2017-02-01 00:00:00
abstract::MicroRNAs (miRNAs) regulate many aspects of human biology. They target mRNAs for translational repression or degradation through base pairing with 3' untranslated regions, primarily via seed sequences (nucleotides 2 to 8 in the mature miRNA sequence). A number of individual miRNAs and miRNA families share seed sequenc...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3006840
更新日期:2013-11-20 00:00:00
abstract::Gene therapy is emerging as a therapeutic modality for treating disorders of the retina. Photoreceptor cells are the primary cell type affected in many inherited diseases of retinal degeneration. Successfully treating these diseases with gene therapy requires the identification of efficient and safe targeting vectors ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3002103
更新日期:2011-06-22 00:00:00
abstract::The recent Perspective entitled "Power of rare diseases: Found in translation" undervalues the contributions of academic research in first-in-human studies. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.3007911
更新日期:2014-01-15 00:00:00
abstract::Lapatinib, a dual HER2/EGFR (human epidermal growth factor receptor 2/epidermal growth factor receptor) inhibitor, is a recently approved targeted therapy for metastatic breast cancer. Because lapatinib enhances the efficacy of the chemotherapeutic agent capecitabine in breast cancer patients, we tested whether lapati...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001384
更新日期:2011-06-08 00:00:00
abstract::Much of our knowledge of the mechanisms underlying plasticity in the visual cortex in response to visual impairment, vision restoration, and environmental interactions comes from animal studies. We evaluated human brain plasticity in a group of patients with Leber's congenital amaurosis (LCA), who regained vision thro...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaa8791
更新日期:2015-07-15 00:00:00
abstract::A congenital or iatrogenic tissue defect often requires closure by open surgery or metallic components that can erode tissue. Biodegradable, hydrophobic light-activated adhesives represent an attractive alternative to sutures, but lack a specifically designed minimally invasive delivery tool, which limits their clinic...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaa2406
更新日期:2015-09-23 00:00:00
abstract::Fibroblasts are primary cellular protagonists of wound healing. They also exhibit circadian timekeeping, which imparts an approximately 24-hour rhythm to their biological function. We interrogated the functional consequences of the cell-autonomous clockwork in fibroblasts using a proteome-wide screen for rhythmically ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aal2774
更新日期:2017-11-08 00:00:00
abstract::Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Ago...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aar3483
更新日期:2018-08-29 00:00:00
abstract::Atherosclerosis is the cause of morbiditiy for 70% of patients with type 2 diabetes. In both of these diseases, a protein complex known as the inflammasome is stimulated to activate interleukin-1β (IL-1β) and IL-18, which are pathogenic inflammatory cytokines. Triggers for the inflammasome are obesity-related factors,...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001902
更新日期:2011-05-04 00:00:00
abstract::KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw7999
更新日期:2019-09-18 00:00:00
abstract::Variants in the leucine-rich repeat kinase-2 (LRRK2) gene are associated with Parkinson's disease, leprosy, and Crohn's disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested t...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aas9292
更新日期:2019-09-25 00:00:00
abstract::Bactericidal antibiotics with diverse mechanisms of action induce generation of mitochondrial reactive oxygen species in mammalian cells (Kalghatgi et al., this issue). ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3006567
更新日期:2013-07-03 00:00:00
abstract::With continued advances in science and technology, there is great potential to extend our healthspan as we age. ...
journal_title:Science translational medicine
pub_type: 社论
doi:10.1126/scitranslmed.abd3816
更新日期:2020-10-21 00:00:00
abstract::Pharmacokinetic and pharmacodynamic models estimate the potency of antiviral agents but do not capture viral and immunologic factors that drive the natural dynamics of infection. We designed a mathematical model that synthesizes pharmacokinetics, pharmacodynamics, and viral pathogenesis concepts to simulate the activi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aad6654
更新日期:2016-02-03 00:00:00
abstract::A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell-dependent b...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aat5775
更新日期:2018-10-17 00:00:00
abstract::Pluripotent stem cells are a scalable source of pancreatic cells for transplantation into patients with diabetes. Here, we describe how the field is gaining momentum toward a β cell replacement therapy. ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaa9359
更新日期:2015-12-02 00:00:00
abstract::The mechanisms by which some HIV-infected subjects resist disease progression, whereas others progress rapidly, are incompletely understood. Viral and host genetic factors, such as nef deletions and major histocompatibility complex alleles, explain a portion of the observed variability. However, it has been difficult ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3003941
更新日期:2012-05-30 00:00:00
abstract::Increased iron in cancer cells drives selective sensitization of tumors to ascorbate treatment to prolong survival. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aan2778
更新日期:2017-04-12 00:00:00
abstract::A new type of biological clock regulates the unfolded protein response. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aan6728
更新日期:2017-06-28 00:00:00