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Giuliana De Gregoriis, Juliene Antonio Ramos, Priscila Valverde Fernandes, Giselle Maria Vignal, Rafael Canfield Brianese, Dirce Maria Carraro, Alvaro N Monteiro, Claudio José Struchiner, Guilherme Suarez-Kurtz, Rosane Vianna-Jorge, Marcelo Alex de Carvalho
Despite remarkable advances in diagnosis, prognosis and treatment, advanced or recurrent breast tumors have limited therapeutic approaches. Many treatment strategies try to explore the limitations of DNA damage response (DDR) in tumor cells to selectively eliminate them. BRCT (BRCA1 C-terminal) domains are present in a superfamily of proteins involved in cell cycle checkpoints and the DDR. Tandem BRCT domains (tBRCT) represent a distinct class of these domains. We investigated the expression profile of 7 tBRCT genes (BARD1, BRCA1, LIG4, ECT2, MDC1, PAXIP1/PTIP and TP53BP1) in breast cancer specimens and observed a high correlation between PAXIP1 and TP53BP1 gene expression in tumor samples...
May 5, 2017: Cancer Biology & Therapy
Shusheng Leng, Mingyang Yang, Yanhua Zhao, Jingfeng Zhao, Zhijun Zeng, Yunpeng Yang, Jiatian Yuan, Bo Lv, Fan Jun, Bing Wang
Hepatocellular carcinoma (HCC) is one of the most lethal tumors worldwide, which is mainly due to the high recurrence and metastasis rate after hepatectomy. In this study, we found that PTIP expression was dramatically upregulated in human HCC tissues and cell lines. High expression of PTIP was shown to be associated with aggressive clinicopathological features, including liver cirrhosis, vascular invasion and advanced stage. In addition, PTIP overexpression was independently associated with shorter survival and increased HCC recurrence in patients...
March 22, 2017: Oncotarget
Stephanie A Freel, Paige C Smith, Ebony N Burns, Joanna B Downer, Ann J Brown, Mark W Dewhirst
PROBLEM: Junior faculty face challenges in establishing independent research careers. Declining funding combined with a shift to multidisciplinary, collaborative science necessitates new mentorship models and enhanced institutional support. APPROACH: Two multidisciplinary mentorship programs to promote grant success for junior faculty were established at the Duke University School of Medicine beginning in 2011. These four-month programs-the Path to Independence Program (PtIP) for National Institutes of Health (NIH) R applicants and the K Club for NIH K applicants-use multiple senior faculty mentors and professional grant-writing staff to provide a 20-hour joint curriculum comprising a series of lectures, hands-on workshops, career development counseling, peer groups, and an internal study section...
March 7, 2017: Academic Medicine: Journal of the Association of American Medical Colleges
Aili Zhang, Bo Peng, Ping Huang, Junjie Chen, Zihua Gong
The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients...
April 21, 2017: Journal of Biological Chemistry
(no author information available yet)
Replication fork protection reduces chemosensitivity in BRCA-deficient cells without restoring HR.
September 2016: Cancer Discovery
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks...
July 21, 2016: Nature
Pierre-Alain Hueber, Monica Salgado Diaz, Yann Chaussy, Julie Franc-Guimond, Diego Barrieras, Anne-Marie Houle
INTRODUCTION: A variety of techniques are available for proximal hypospadias repair. Onlay, proximal tubularized incised plate (TIP), and Duckett are among the popular choices because they can be performed as a one-step procedure. However, the decision to select a procedure often comes down to the surgeon's preference rather than that supported by evidence-based data. In particular, there is a paucity of literature on the long-term urinary outcomes after proximal hypospadias repair. OBJECTIVE: The aim of this study was to evaluate the evolution of long-term uroflowmetry parameters after proximal hypospadias surgery over a long-term follow-up including the adolescent period...
August 2016: Journal of Pediatric Urology
Linda M Starnes, Dan Su, Laura M Pikkupeura, Brian T Weinert, Margarida A Santos, Andreas Mund, Rebeca Soria, Young-Wook Cho, Irina Pozdnyakova, Martina Kubec Højfeldt, Andrea Vala, Wenjing Yang, Blanca López-Méndez, Ji-Eun Lee, Weiqun Peng, Joan Yuan, Kai Ge, Guillermo Montoya, André Nussenzweig, Chunaram Choudhary, Jeremy A Daniel
Class switch recombination (CSR) diversifies antibodies for productive immune responses while maintaining stability of the B-cell genome. Transcription at the immunoglobulin heavy chain (Igh) locus targets CSR-associated DNA damage and is promoted by the BRCT domain-containing PTIP (Pax transactivation domain-interacting protein). Although PTIP is a unique component of the mixed-lineage leukemia 3 (MLL3)/MLL4 chromatin-modifying complex, the mechanisms for how PTIP promotes transcription remain unclear. Here we dissected the minimal structural requirements of PTIP and its different protein complexes using quantitative proteomics in primary lymphocytes...
January 15, 2016: Genes & Development
Eva Mejia-Ramirez, Oliver Limbo, Petra Langerak, Paul Russell
Phosphorylation of histone H2AX by ATM and ATR establishes a chromatin recruitment platform for DNA damage response proteins. Phospho-H2AX (γH2AX) has been most intensively studied in the context of DNA double-strand breaks caused by exogenous clastogens, but recent studies suggest that DNA replication stress also triggers formation of γH2A (ortholog of γH2AX) in Schizosaccharomyces pombe. Here, a focused genetic screen in fission yeast reveals that γH2A is critical when there are defects in Replication Factor C (RFC), which loads proliferating cell nuclear antigen (PCNA) clamp onto duplex DNA...
September 2015: PLoS Genetics
Adam B Stein, Sascha N Goonewardena, Thomas A Jones, Parker J Prusick, Ahmad A Bazzi, Jane M Belyavskaya, Makayla M McCoskey, Rachel A Dandar
Pressure overload induces stress-induced signaling pathways and a coordinated transcriptional response that begets concentric cardiac hypertrophy. Although concentric hypertrophy initially attenuates wall stress and maintains cardiac function, continued stress can result in maladaptive cardiac remodeling. Cardiac remodeling is orchestrated by transcription factors that act within the context of an epigenetic landscape. Since the epigenetic landscape serves as a molecular link between environmental factors (stress) and cellular phenotype (disease), defining the role of the epigenome in the development and progression of cardiac remodeling could lead to new therapeutic approaches...
2015: PloS One
Vera Boersma, Nathalie Moatti, Sandra Segura-Bayona, Marieke H Peuscher, Jaco van der Torre, Brigitte A Wevers, Alexandre Orthwein, Daniel Durocher, Jacqueline J L Jacobs
Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability...
May 28, 2015: Nature
Saji Abraham, Raghavendra Paknikar, Samina Bhumbra, Danny Luan, Rohan Garg, Gregory R Dressler, Sanjeevkumar R Patel
Pax genes encode developmental regulatory proteins that specify cell lineages and tissues in metazoans. Upon binding to DNA through the conserved paired domain, Pax proteins can recruit both activating and repressing complexes that imprint distinct patterns of histone methylation associated with either gene activation or silencing. How the switch from Pax-mediated activation to repression is regulated remains poorly understood. In this report, we identify the phosphatase PPM1B as an essential component of the Groucho4 repressor complex that is recruited by Pax2 to chromatin...
March 13, 2015: Journal of Biological Chemistry
Egon J Ranghini, Gregory R Dressler
Activation of the Pax2 gene marks the intermediate mesoderm shortly after gastrulation, as the mesoderm becomes compartmentalized into paraxial, intermediate, and lateral plate. Using an EGFP knock-in allele of Pax2 to identify and sort cells of the intermediate mesodermal lineage, we compared gene expression patterns in EGFP positive cells that were heterozygous or homozygous null for Pax2. Thus, we identified critical regulators of intermediate mesoderm and kidney development whose expression depended on Pax2 function...
March 15, 2015: Developmental Biology
Mazhar Adli, Mahmut Parlak, Yuwen Li, Samir S El-Dahr
In mammals, formation of new nephrons ends perinatally due to consumption of mesenchymal progenitor cells. Premature depletion of progenitors due to prematurity or postnatal loss of nephrons due to injury causes chronic kidney disease and hypertension. Intensive efforts are currently invested in designing regenerative strategies to form new nephron progenitors from pluripotent cells, which upon further differentiation provide a potential source of new nephrons. To know if reprogramed renal cells can maintain their identity and fate requires knowledge of the epigenetic states of native nephron progenitors and their progeny...
June 2015: Journal of Cellular Biochemistry
Jiadong Wang, Asaithamby Aroumougame, Markus Lobrich, Yujing Li, David Chen, Junjie Chen, Zihua Gong
PARP inhibitors (PARPis) are being used in patients with BRCA1/2 mutations. However, doubly deficient BRCA1(-/-)53BP1(-/-) cells or tumors become resistant to PARPis. Since 53BP1 or its known downstream effectors, PTIP and RIF1 (RAP1-interacting factor 1 homolog), lack enzymatic activities directly implicated in DNA repair, we decided to further explore the 53BP1-dependent pathway. In this study, we uncovered a nuclease, Artemis, as a PTIP-binding protein. Loss of Artemis restores PARPi resistance in BRCA1-deficient cells...
December 15, 2014: Genes & Development
Björn Salomonsson
This article critically examines the existent evidence base for Psychodynamic Therapy with Infants and Parents (PTIP), specifically focusing on the available RCTs (Randomized Controlled Trials) in the literature. The author also discusses how these studies influenced the design of an RCT of a related novel treatment method, Mother-Infant Psychoanalytic treatment (MIP). He found that certain types of mothers and infants may be more likely to benefit from MIP. In addition to providing guidance on therapeutic techniques, this article also effectively outlines ways in which PTIP, as well as psychotherapy for emotional issues during pregnancy, can be better integrated into the comprehensive health care system...
December 2014: Psychodynamic Psychiatry
Björn Salomonsson
The theory of psychoanalysis has always relied on speculations about the infant's mind, but its clinical practice was slow in taking an interest in babies and their parents. The therapy methods that nevertheless have evolved during the last 50 years differ in their emphasis on support or insight, which roles they attribute to mother and baby in therapy, and to what extent they focus on the unconscious influences in mother and baby, respectively. They also differ to what extent their theories rely on classical psychoanalysis, attachment psychology, developmental psychology, and infant research...
June 2014: Psychodynamic Psychiatry
A Srishailam, Yata Praveen Kumar, P Venkat Reddy, Navaneetha Nambigari, Uma Vuruputuri, Surya S Singh, S Satyanarayana
Three new mononuclear [Ru (phen)2 ptip](2+) (1), [Ru (bpy)2 ptip](2+) (2) and [Ru (dmb)2 ptip](2+) (3) [ptip=(2-(5-phenylthiophen-2-yl)-1H-imidazo[4, 5-f][1,10 phenanthroline, phen=1, 10 phenanthroline, bpy=2, 2' bipyridine, dmb=4, 4'-dimethyl 2, 2' bipyridine] complexes were synthesized and characterised by elemental analysis, IR, NMR and Mass spectra. The DNA-binding behaviours were investigated by electronic absorption titration, luminescence spectra, viscosity measurements and photo-activated cleavage. The DNA-binding constants Kb of complexes 1, 2 and 3 were determined to be 7...
March 5, 2014: Journal of Photochemistry and Photobiology. B, Biology
Yan Liu, Yue Huang, Jun Fan, Guo-Zhang Zhu
Pituitary homeobox 2 (PITX2), a Paired-like homeodomain transcription factor and a downstream effector of Wnt/β-catenin signaling, plays substantial roles in embryonic development and human disorders. The mechanism of its functions, however, is not fully understood. In this study, we demonstrated that PITX2 associated with histone H3 lysine 4 (H3K4) methyltransferase (HKMT) mixed-lineage leukemia 4 (MLL4/KMT2D), Pax transactivation domain-interacting protein (PTIP), and other H3K4·HKMT core subunits. This association of PITX2 with H3K4·HKMT complex was dependent on PITX2's homeodomain...
February 21, 2014: Biochemical and Biophysical Research Communications
Takashi Takeshita, Mutsuko Yamamoto-Ibusuki, Yutaka Yamamoto, Yoko Omoto, Yumi Honda, Ken-ichi Iyama, Zhenhuan Zhang, Hirotaka Iwase
Pax transactivation domain interacting protein (PTIP) associated protein 1, PA1, was a newly found protein participating in the modulation of transactivity of nuclear receptor super family members such as estrogen receptor (ER), androgen receptor (AR) and glucocorticoid receptor (GR). Breast cancer is one of the most life threatening diseases for women and has tight association with estrogen and ER. This study was performed to understand the function of PA1 in breast cancer. The expression of PA1 had been evaluated in a total of 344 primary invasive breast cancer samples and examined the relationship with clinical output, relapse free survival (RFS), breast cancer-specific survival (BCSS)...
2013: PloS One
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