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  • 1
    Publication Date: 2018-01-03
    Description: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2 + metastatic breast cancer; however, its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2 + tumors, are not well understood. We used HER2 + cell lines to develop models of T-DM1 resistance using a cyclical dosing schema in which cells received T-DM1 in an "on-off" routine until a T-DM1–resistant population was generated. T-DM1–resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non–cleavable-linked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g., MDR1) expression compared with parental N87 cells. Intriguingly, T-ADCs using auristatin payloads attached via an enzymatically cleavable linker overcome T-DM1 resistance in N87-TM cells. Importantly, N87-TM cells implanted into athymic mice formed T-DM1 refractory tumors that remain sensitive to T-ADCs with cleavable-linked auristatin payloads. Comparative proteomic profiling suggested enrichment in proteins that mediate caveolae formation and endocytosis in the N87-TM cells. Indeed, N87-TM cells internalize T-ADCs into intracellular caveolin-1 (CAV1)–positive puncta and alter their trafficking to the lysosome compared with N87 cells. T-DM1 colocalization into intracellular CAV1-positive puncta correlated with reduced response to T-DM1 in a panel of HER2 + cell lines. Together, these data suggest that caveolae-mediated endocytosis of T-DM1 may serve as a novel predictive biomarker for patient response to T-DM1. Mol Cancer Ther; 17(1); 243–53. ©2017 AACR .
    Print ISSN: 1535-7163
    Electronic ISSN: 1538-8514
    Topics: Medicine
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  • 2
    Keywords: CLASSIFICATION ; TUMORS ; WOMEN ; HEIGHT ; METAANALYSIS ; BODY-MASS INDEX ; PREMENOPAUSAL ; SEX-HORMONES ; SELF-REPORTED WEIGHT ; HORMONE-THERAPY
    Abstract: Whilst previous studies have reported that higher BMI increases a woman's risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13 548 cases and 17 913 controls). We combined study-specific adjusted odds ratios (ORs) using a random-effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5 kg/m(2); 95% CI 1.18-1.30), invasive endometrioid (1.17; 1.11-1.23) and invasive mucinous (1.19; 1.06-1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94-1.02), but increased risks for low-grade serous invasive tumours (1.13, 1.03-1.25) and in pre-menopausal women (1.11; 1.04-1.18). Among post-menopausal women, the associations did not differ between hormone replacement therapy users and non-users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high-grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.
    Type of Publication: Journal article published
    PubMed ID: 23404857
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  • 3
    Publication Date: 2011-12-17
    Description: Hox proteins are a metazoan-specific family of transcription factors that are required for developmental patterning. The genomic arrangement of Hox genes into four paralogous clusters is a primitive feature of jawed vertebrates. By using high-throughput sequencing, we demonstrate the absence of all HoxC transcripts from embryos of the shark Scyliorhinus canicula and the skate Leucoraja erinacea and the absence of all HoxC genes and two HoxC-associated microRNAs from the genome of L. erinacea. These data suggest a loss of the entire HoxC cluster in elasmobranch fishes and represent evidence for the natural deletion of an entire Hox cluster in vertebrates.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264428/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264428/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉King, Benjamin L -- Gillis, J Andrew -- Carlisle, Heather R -- Dahn, Randall D -- P20 RR016463/RR/NCRR NIH HHS/ -- P20 RR016463-12/RR/NCRR NIH HHS/ -- P20RR016463/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2011 Dec 16;334(6062):1517. doi: 10.1126/science.1210912.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Kathryn W. Davis Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, USA. bking@mdibl.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22174244" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Gene Deletion ; Gene Silencing ; Homeodomain Proteins/*genetics ; MicroRNAs/genetics ; Multigene Family ; Sharks/*genetics ; Skates (Fish)/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2013-11-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bolukbasi, Burcu -- Berente, Nicholas -- Cutcher-Gershenfeld, Joel -- Dechurch, Leslie -- Flint, Courtney -- Haberman, Michael -- King, John Leslie -- Knight, Eric -- Lawrence, Barbara -- Masella, Ethan -- McElroy, Charles -- Mittleman, Barbara -- Nolan, Mark -- Radik, Melanie -- Shin, Namchul -- Thompson, Cheryl A -- Winter, Susan -- Zaslavsky, Ilya -- Allison, M Lee -- Arctur, David -- Arrigo, Jennifer -- Aufdenkampe, Anthony K -- Bass, Jay -- Crowell, Jim -- Daniels, Mike -- Diggs, Stephen -- Duffy, Christopher -- Gil, Yolanda -- Gomez, Basil -- Graves, Sara -- Hazen, Robert -- Hsu, Leslie -- Kinkade, Danie -- Lehnert, Kerstin -- Marone, Chris -- Middleton, Don -- Noren, Anders -- Pearthree, Genevieve -- Ramamurthy, Mohan -- Robinson, Erin -- Percivall, George -- Richard, Stephen -- Suarez, Celina -- Walker, Doug -- New York, N.Y. -- Science. 2013 Nov 29;342(6162):1041-2. doi: 10.1126/science.342.6162.1041-b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Labor and Employment Relations, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24288316" target="_blank"〉PubMed〈/a〉
    Keywords: *Access to Information ; Periodicals as Topic/*economics ; Research/*economics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2016-03-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McNutt, Marcia -- Lehnert, Kerstin -- Hanson, Brooks -- Nosek, Brian A -- Ellison, Aaron M -- King, John Leslie -- New York, N.Y. -- Science. 2016 Mar 4;351(6277):1024-6. doi: 10.1126/science.aad7048. Epub 2016 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Editor-in-Chief, Science, Washington, DC 20005 USA. mmcnutt@aaas.org. ; Columbia University, Palisades, NY 10964 USA. ; American Geophysical Union, Washington, DC 20009 USA. ; University of Virginia and Center for Open Science, Charlottesville, VA 22903 USA. ; Harvard University, Petersham, MA 01366 USA. ; University of Michigan, Ann Arbor, MI 48109 USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26941302" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2018-05-19
    Description: Proteolytic processing is an irreversible post-translational modification functioning as a ubiquitous regulator of cellular activity. Protease activity is tightly regulated via control of gene expression, enzyme and substrate compartmentalization, zymogen activation, enzyme inactivation, and substrate availability. Emerging evidence suggests that proteolysis can also be regulated by substrate glycosylation and that glycosylation of individual sites on a substrate can decrease or, in rare cases, increase its sensitivity to proteolysis. Here, we investigated the relationship between site-specific, mucin-type (or GalNAc-type) O-glycosylation and proteolytic cleavage of extracellular proteins. Using in silico analysis, we found that O-glycosylation and cleavage sites are significantly associated with each other. We then used a positional proteomic strategy, terminal amine isotopic labeling of substrates (TAILS), to map the in vivo cleavage sites in HepG2 SimpleCells with and without one of the key initiating GalNAc transferases, GalNAc-T2, and after treatment with exogenous matrix metalloproteinase 9 (MMP9) or neutrophil elastase. Surprisingly, we found that loss of GalNAc-T2 not only increased cleavage, but also decreased cleavage across a broad range of other substrates, including key regulators of the protease network. We also found altered processing of several central regulators of lipid homeostasis, including apolipoprotein B and the phospholipid transfer protein, providing new clues to the previously reported link between GALNT2 and lipid homeostasis. In summary, we show that loss of GalNAc-T2 O-glycosylation leads to a general decrease in cleavage and that GalNAc-T2 O-glycosylation affects key regulators of the cellular proteolytic network, including multiple members of the serpin family.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 7
    Publication Date: 2018-03-06
    Description: Purpose: We hypothesized that axitinib is active with an improved safety profile in nasopharyngeal carcinoma (NPC). Experimental Design: We evaluated axitinib in preclinical models of NPC and studied its efficacy in a phase II clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice daily in continuous 4-week cycles. Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients achieving complete response, partial response, or stable disease by RECIST criteria for more than 3 months. Results: We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) receiving ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI, 65.6%–91.2%) at 3 months and 43.2% (30.4%–56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%), and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during the first 3 months of axitinib treatment was significantly associated with improved overall survival (HR, 0.29; 95% CI, 0.13–0.64, P = 0.0012). Patient-reported fatigue symptom was associated with hypothyroidism ( P = 0.039). Axitinib PK parameters (C max and AUC (0-t) ) were significantly correlated with tumor response, toxicity, and serum thyroid-stimulating hormone changes. Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients. Clin Cancer Res; 24(5); 1030–7. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 8
    Publication Date: 2018-03-13
    Description: Rapid, real time pathology review for ECOG/ACRIN 1412: a novel and successful paradigm for future lymphoma clinical trials in the precision medicine era Rapid, real time pathology review for ECOG/ACRIN 1412: a novel and successful paradigm for future lymphoma clinical trials in the precision medicine era, Published online: 28 February 2018; doi:10.1038/s41408-018-0064-9 Rapid, real time pathology review for ECOG/ACRIN 1412: a novel and successful paradigm for future lymphoma clinical trials in the precision medicine era
    Electronic ISSN: 2044-5385
    Topics: Medicine
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  • 9
    Publication Date: 2018-03-29
    Description: African swine fever virus (ASFV) causes an acute hemorrhagic fever in domestic pigs, with high socioeconomic impact. No vaccine is available, limiting options for control. Although live attenuated ASFV can induce up to 100% protection against lethal challenge, little is known of the antigens which induce this protective response. To identify additional ASFV immunogenic and potentially protective antigens, we cloned 47 viral genes in individual plasmids for gene vaccination and in recombinant vaccinia viruses. These antigens were selected to include proteins with different functions and timing of expression. Pools of up to 22 antigens were delivered by DNA prime and recombinant vaccinia virus boost to groups of pigs. Responses of immune lymphocytes from pigs to individual recombinant proteins and to ASFV were measured by interferon gamma enzyme-linked immunosorbent spot (ELISpot) assays to identify a subset of the antigens that consistently induced the highest responses. All 47 antigens were then delivered to pigs by DNA prime and recombinant vaccinia virus boost, and pigs were challenged with a lethal dose of ASFV isolate Georgia 2007/1. Although pigs developed clinical and pathological signs consistent with acute ASFV, viral genome levels were significantly reduced in blood and several lymph tissues in those pigs immunized with vectors expressing ASFV antigens compared with the levels in control pigs. IMPORTANCE The lack of a vaccine limits the options to control African swine fever. Advances have been made in the development of genetically modified live attenuated ASFV that can induce protection against challenge. However, there may be safety issues relating to the use of these in the field. There is little information about ASFV antigens that can induce a protective immune response against challenge. We carried out a large screen of 30% of ASFV antigens by delivering individual genes in different pools to pigs by DNA immunization prime and recombinant vaccinia virus boost. The responses in immunized pigs to these individual antigens were compared to identify the most immunogenic. Lethal challenge of pigs immunized with a pool of antigens resulted in reduced levels of virus in blood and lymph tissues compared to those in pigs immunized with control vectors. Novel immunogenic ASFV proteins have been identified for further testing as vaccine candidates.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 10
    Publication Date: 2012-08-04
    Description: Supermassive black holes (SMBHs; mass is greater than or approximately 10(5) times that of the Sun) are known to exist at the center of most galaxies with sufficient stellar mass. In the local universe, it is possible to infer their properties from the surrounding stars or gas. However, at high redshifts we require active, continuous accretion to infer the presence of the SMBHs, which often comes in the form of long-term accretion in active galactic nuclei. SMBHs can also capture and tidally disrupt stars orbiting nearby, resulting in bright flares from otherwise quiescent black holes. Here, we report on a ~200-second x-ray quasi-periodicity around a previously dormant SMBH located in the center of a galaxy at redshift z = 0.3534. This result may open the possibility of probing general relativity beyond our local universe.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reis, R C -- Miller, J M -- Reynolds, M T -- Gultekin, K -- Maitra, D -- King, A L -- Strohmayer, T E -- New York, N.Y. -- Science. 2012 Aug 24;337(6097):949-51. doi: 10.1126/science.1223940. Epub 2012 Aug 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Astronomy, University of Michigan, Ann Arbor, MI 48109, USA. rdosreis@umich.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22859817" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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