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https://www.readbyqxmd.com/read/28339723/leveraging-molecular-datasets-for-biomarker-based-clinical-trial-design-in-glioblastoma
#1
Shyam K Tanguturi, Lorenzo Trippa, Shakti H Ramkissoon, Kristine Pelton, David Knoff, David Sandak, Neal I Lindeman, Azra H Ligon, Rameen Beroukhim, Giovanni Parmigiani, Patrick Y Wen, Keith L Ligon, Brian M Alexander
Background.: Biomarkers can improve clinical trial efficiency, but designing and interpreting biomarker-driven trials require knowledge of relationships among biomarkers, clinical covariates, and endpoints. We investigated these relationships across genomic subgroups of glioblastoma (GBM) within our institution (DF/BWCC), validated results in The Cancer Genome Atlas (TCGA), and demonstrated potential impacts on clinical trial design and interpretation. Methods.: We identified genotyped patients at DF/BWCC, and clinical associations across 4 common GBM genomic biomarker groups were compared along with overall survival (OS), progression-free survival (PFS), and survival post-progression (SPP)...
February 20, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28339050/p53-mutation-status-is-a-primary-determinant-of-placenta-specific-protein-1-expression-in-serous-ovarian-cancers
#2
Eric J Devor, Jesus Gonzalez-Bosquet, Akshaya Warrier, Henry D Reyes, Nonye V Ibik, Brandon M Schickling, Andreea Newtson, Michael J Goodheart, Kimberly K Leslie
Placenta-specific protein 1 (PLAC1) expression is co-opted in numerous human cancers. As a consequence of PLAC1 expression, tumor cells exhibit enhanced proliferation and invasiveness. This characteristic is associated with increased aggressiveness and worse patient outcomes. Recently, the presence of the tumor suppressor p53 was shown in vitro to inhibit PLAC1 transcription by compromising the P1, or distal/cancer, promoter. We sought to determine if this phenomenon occurs in primary patient tumors as well...
March 23, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28338653/breast-ductal-carcinoma-in-situ-carry-mutational-driver-events-representative-of-invasive-breast-cancer
#3
Jia-Min B Pang, Peter Savas, Andrew P Fellowes, Gisela Mir Arnau, Tanjina Kader, Ravikiran Vedururu, Chelsee Hewitt, Elena A Takano, David J Byrne, David Yh Choong, Ewan Ka Millar, C Soon Lee, Sandra A O'Toole, Sunil R Lakhani, Margaret C Cummings, G Bruce Mann, Ian G Campbell, Alexander Dobrovic, Sherene Loi, Kylie L Gorringe, Stephen B Fox
The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30)...
March 24, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28337243/residue-specific-interactions-of-an-intrinsically-disordered-protein-with-silica-nanoparticles-and-their-quantitative-prediction
#4
Mouzhe Xie, Alexandar L Hansen, Jiaqi Yuan, Rafael Brüschweiler
Elucidation of the driving forces that govern interactions between nanoparticles and intrinsically disordered proteins (IDP) is important for the understanding of the effect of nanoparticles in living systems and for the design of new nanoparticle-based assays to monitor health and combat disease. The quantitative interaction profile of the intrinsically disordered transactivation domain of p53 and its mutants with anionic silica nanoparticles is reported at atomic resolution using nuclear magnetic spin relaxation experiments...
October 27, 2016: Journal of Physical Chemistry. C, Nanomaterials and Interfaces
https://www.readbyqxmd.com/read/28336806/fluorouracil-enhances-photodynamic-therapy-of-squamous-cell-carcinoma-via-a-p53-independent-mechanism-that-increases-protoporphyrin-ix-levels-and-tumor-cell-death
#5
Sanjay Anand, Kishore R Rollakanti, Niokelta Brankov, Douglas E Brash, Tayyaba Hasan, Edward V Maytin
Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) to drive synthesis of protoporphryin IX (PpIX) is a promising, scar-free alternative to surgery for skin cancers, including squamous cell carcinoma (SCC) and SCC precursors called actinic keratoses (AK). In the United States, PDT is only FDA approved for treatment of AK; this narrow range of indications could be broadened if PDT efficacy were improved. Toward that goal, we developed a mechanism-based combination approach using 5-fluorouracil (5-FU) as a neoadjuvant for ALA-based PDT...
March 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28334334/p53-and-its-mutants-on-the-slippery-road-from-stemness-to-carcinogenesis
#6
Alina Molchadsky, Varda Rotter
Normal development, tissue homeostasis and regeneration following injury rely on the proper functions of wide repertoire of stem cells (SCs) persisting during embryonic period and throughout the adult life. Therefore, SCs employ robust mechanisms to preserve their genomic integrity and avoid heritage of mutations to their daughter cells. Importantly, propagation of SCs with faulty DNA as well as dedifferentiation of genomically altered somatic cells may result in derivation of cancer SCs, which are considered to be the driving force of the tumorigenic process...
March 15, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28333150/kaiso-depletion-attenuates-the-growth-and-survival-of-triple-negative-breast-cancer-cells
#7
Blessing I Bassey-Archibong, Lyndsay G A Rayner, Shawn M Hercules, Craig W Aarts, Anna Dvorkin-Gheva, Jonathan L Bramson, John A Hassell, Juliet M Daniel
Triple negative breast cancers (TNBC) are highly aggressive and lack specific targeted therapies. Recent studies have reported high expression of the transcription factor Kaiso in triple negative tumors, and this correlates with their increased aggressiveness. However, little is known about the clinical relevance of Kaiso in the growth and survival of TNBCs. Herein, we report that Kaiso depletion attenuates TNBC cell proliferation, and delays tumor onset in mice xenografted with the aggressive MDA-231 breast tumor cells...
March 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28324505/probing-the-telomere-damage-response
#8
Rekha Rai, Sandy Chang
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the removal of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases, and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant-negative mutant TPP1ΔRD, can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28320780/thiosemicarbazones-functioning-as-zinc-metallochaperones-to-reactivate-mutant-p53
#9
Xin Yu, Adam R Blanden, Ashley Tsang, Saif Zaman, Yue Liu, John Gilleran, Anthony F Bencivenga, S David Kimball, Stewart N Loh, Darren R Carpizo
Small molecule restoration of wild type structure and function to mutant p53 (so - called mutant reactivation) is a highly sought after goal in cancer drug development. We previously discovered small molecule zinc chelators called zinc metallochaperones (ZMCs) reactivate mutant p53 by restoring zinc binding to zinc deficient p53 mutants. The lead compound identified from the NCI-60 human tumor cell lines screen, NSC319726 (ZMC1), belongs to the thiosemicarbazone (TSC) class of metal ion chelators that bind Fe, Cu, Mn, Zn, and other transition metals...
March 20, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28320736/arabidopsis-retinoblastoma-related-directly-regulates-dna-damage-responses-through-functions-beyond-cell-cycle-control
#10
Beatrix M Horvath, Hana Kourova, Szilvia Nagy, Edit Nemeth, Zoltan Magyar, Csaba Papdi, Zaki Ahmad, Gabino F Sanchez-Perez, Serena Perilli, Ikram Blilou, Aladár Pettkó-Szandtner, Zsuzsanna Darula, Tamas Meszaros, Pavla Binarova, Laszlo Bogre, Ben Scheres
The rapidly proliferating cells in plant meristems must be protected from genome damage. Here, we show that the regulatory role of the Arabidopsis RETINOBLASTOMA RELATED (RBR) in cell proliferation can be separated from a novel function in safeguarding genome integrity. Upon DNA damage, RBR and its binding partner E2FA are recruited to heterochromatic γH2AX-labelled DNA damage foci in an ATM- and ATR-dependent manner. These γH2AX-labelled DNA lesions are more dispersedly occupied by the conserved repair protein, AtBRCA1, which can also co-localise with RBR foci...
March 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28300842/cd95-ligand-induces-senescence-in-mismatch-repair-deficient-human-colon-cancer-via-chronic-caspase-mediated-induction-of-dna-damage
#11
Danielle A Raats, Nicola Frenkel, Susanne J van Schelven, Inne HMBorel Rinkes, Jamila Laoukili, Onno Kranenburg
CD95 is best known for its ability to induce apoptosis via a well-characterized pathway involving caspase-mediated proteolytic events. However, in apoptosis-resistant cell lines of diverse cancer types stimulation of CD95 primarily has pro-tumorigenic effects that affect many of the hallmarks of cancer. For instance, in colon cancer cells with a mutant KRAS gene CD95 primarily promotes invasion and metastasis. In the current study, we further investigated the context dependency of the consequences of CD95 activation in colon cancer...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28300840/ganetespib-synergizes-with-cyclophosphamide-to-improve-survival-of-mice-with-autochthonous-tumors-in-a-mutant-p53-dependent-manner
#12
Evguenia M Alexandrova, Sulan Xu, Ute M Moll
The DNA-alkylating cytotoxic agent cyclophosphamide (CTX) is commonly used in the clinic to treat hematological malignancies like lymphomas and leukemias as well as solid tumors, but shows dose-dependent potentially life-threatening toxicities and can induce secondary malignancies. Thus, the clinical utility of CTX would be improved if a companion drug could be identified that allows lowering the CTX dose, while maintaining or even increasing its antineoplastic therapeutic efficacy. In mouse models, high-dose CTX (300 mg/kg) is effective in treating T-lymphomas, while low dose (defined here as 100 mg/kg) is ineffective...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28299662/the-runx-genes-as-conditional-oncogenes-insights-from-retroviral-targeting-and-mouse-models
#13
James C Neil, Kathryn Gilroy, Gillian Borland, Jodie Hay, Anne Terry, Anna Kilbey
The observation that the Runx genes act as targets for transcriptional activation by retroviral insertion identified a new family of dominant oncogenes. However, it is now clear that Runx genes are 'conditional' oncogenes whose over-expression is growth inhibitory unless accompanied by another event such as concomitant over-expression of MYC or loss of p53 function. Remarkably, while the oncogenic activities of either MYC or RUNX over-expression are suppressed while p53 is intact, the combination of both neutralises p53 tumour suppression in vivo by as yet unknown mechanisms...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28294943/a-team-of-heterochromatin-factors-collaborates-with-small-rna-pathways-to-combat-repetitive-elements-and-germline-stress
#14
Alicia N McMurchy, Przemyslaw Stempor, Tessa Gaarenstroom, Brian Wysolmerski, Yan Dong, Darya Aussianikava, Alex Appert, Ni Huang, Paulina Kolasinska-Zwierz, Alexandra Sapetschnig, Eric A Miska, Julie Ahringer
Repetitive sequences derived from transposons make up a large fraction of eukaryotic genomes and must be silenced to protect genome integrity. Repetitive elements are often found in heterochromatin; however, the roles and interactions of heterochromatin proteins in repeat regulation are poorly understood. Here we show that a diverse set of C. elegans heterochromatin proteins act together with the piRNA and nuclear RNAi pathways to silence repetitive elements and prevent genotoxic stress in the germ line. Mutants in genes encoding HPL-2/HP1, LIN-13, LIN-61, LET-418/Mi-2, and H3K9me2 histone methyltransferase MET-2/SETDB1 also show functionally redundant sterility, increased germline apoptosis, DNA repair defects, and interactions with small RNA pathways...
March 15, 2017: ELife
https://www.readbyqxmd.com/read/28292898/multisite-aggregation-of-p53-and-implications-for-drug-rescue
#15
GuoZhen Wang, Alan R Fersht
Protein aggregation is involved in many diseases. Often, a unique aggregation-prone sequence polymerizes to form regular fibrils. Many oncogenic mutants of the tumor suppressor p53 rapidly aggregate but form amorphous fibrils. A peptide surrounding Ile254 is proposed to be the aggregation-driving sequence in cells. We identified several different aggregating sites from limited proteolysis of harvested aggregates and effects of mutations on kinetics and products of aggregation. We present a model whereby the amorphous nature of the aggregates results from multisite branching of polymerization after slow unfolding of the protein, which may be a common feature of aggregation of large proteins...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28292018/vitis-vinifera-peel-and-seed-gold-nanoparticles-exhibit-chemopreventive-potential-antioxidant-activity-and-induce-apoptosis-through-mutant-p53-bcl-2-and-pan-cytokeratin-down-regulation-in-experimental-animals
#16
J Grace Nirmala, R T Narendhirakannan
Several studies suggest surface modifications of gold nanoparticles (AuNPs) by capping agents or surface coatings could play an important role in biological systems, and site directed delivery. The present study was carried out to assess the antioxidant and apoptotic activities of the Vitis vinifera peel and seed gold nanoparticles in experimentally induced cancer in Swiss albino mice. 12-dimethylbenz [a] anthracene (DMBA) (single application) and 12-O-tetradecanoylphorbol 13-acetate (TPA) (thrice a week) were applied on the dorsal area of the skin to induce skin papillomagenesis in Swiss albino mice for 16 weeks...
March 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28292017/-curine-induces-cell-cycle-arrest-and-cell-death-in-hepatocellular-carcinoma-cells-in-a-p53-independent-way
#17
Shu Gong, Dongsheng Xu, Fangdong Zou, Rui Peng
Hepatocellular carcinoma(HCC) is one of the most common malignancies worldwide, however, drug resistance is still a tough problem of it. As in many other cancers, p53 mutations are commonly observed in HCCs (Hussain et al., 2007; Levine et al., 1994) [1,2]. Tumor tissues with mutant p53 seems to be more aggressive and resist to chemotherapy than that harboring wide-type p53 (Harris and Hollstein, 1994; Parrales and Iwakuma, 2015) [3,4]. (-)-Curine, a novel bisbenzylisoquinoline alkaloid, is one of the main components isolated from the roots of Cyclea wattii...
March 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28289710/targeting-adhesion-signaling-in-kras-lkb1-mutant-lung-adenocarcinoma
#18
Melissa Gilbert-Ross, Jessica Konen, Junghui Koo, John Shupe, Brian S Robinson, Walter Guy Wiles, Chunzi Huang, W David Martin, Madhusmita Behera, Geoffrey H Smith, Charles E Hill, Michael R Rossi, Gabriel L Sica, Manali Rupji, Zhengjia Chen, Jeanne Kowalski, Andrea L Kasinski, Suresh S Ramalingam, Haian Fu, Fadlo R Khuri, Wei Zhou, Adam I Marcus
Loss of LKB1 activity is prevalent in KRAS mutant lung adenocarcinoma and promotes aggressive and treatment-resistant tumors. Previous studies have shown that LKB1 is a negative regulator of the focal adhesion kinase (FAK), but in vivo studies testing the efficacy of FAK inhibition in LKB1 mutant cancers are lacking. Here, we took a pharmacologic approach to show that FAK inhibition is an effective early-treatment strategy for this high-risk molecular subtype. We established a lenti-Cre-induced Kras and Lkb1 mutant genetically engineered mouse model (KLLenti) that develops 100% lung adenocarcinoma and showed that high spatiotemporal FAK activation occurs in collective invasive cells that are surrounded by high levels of collagen...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28284059/reactivating-p53-and-inducing-tumor-apoptosis-rita-enhances-the-response-of-rita-sensitive-colorectal-cancer-cells-to-chemotherapeutic-agents-5-fluorouracil-and-oxaliplatin
#19
Armin Wiegering, Niels Matthes, Bettina Mühling, Monika Koospal, Anne Quenzer, Stephanie Peter, Christoph-Thomas Germer, Michael Linnebacher, Christoph Otto
Colorectal carcinoma (CRC) is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU) and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA) is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death...
March 8, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28281901/tp53-and-its-potential-therapeutic-role-as-a-target-in-bladder-cancer
#20
Chiara Ciccarese, Francesco Massari, Ana Blanca, Giampaolo Tortora, Rodolfo Montironi, Liang Cheng, Marina Scarpelli, Maria R Raspollini, Nuno Vau, Jorge Fonseca, Antonio Lopez-Beltran
Despite more than 30 years of research on p53 resulting in >50,000 publications, we are now beginning to figure out the complexity of the p53 pathway, gene ontology and conformational structure of the molecule. Recent years brought great advances in p53 related drugs and the potencial ways in which p53 is inactivated in cancer. Areas covered: We searched for related publications on Pubmed and ClinicalTrial.gov using the following keywords 'p53, Tp53, p53 and bladder cancer, p53 and therapeutic target'. Relevant articles improved the understanding on p53 pathways and their potential as candidate to targeted therapy in bladder cancer...
April 2017: Expert Opinion on Therapeutic Targets
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