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https://www.readbyqxmd.com/read/29138277/coupling-shrna-screens-with-single-cell-rna-seq-identifies-a-dual-role-for-mtor-in-reprogramming-induced-senescence
#1
Marieke Aarts, Athena Georgilis, Meryam Beniazza, Patrizia Beolchi, Ana Banito, Thomas Carroll, Marizela Kulisic, Daniel F Kaemena, Gopuraja Dharmalingam, Nadine Martin, Wolf Reik, Johannes Zuber, Keisuke Kaji, Tamir Chandra, Jesús Gil
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates...
November 14, 2017: Genes & Development
https://www.readbyqxmd.com/read/29125889/pterostilbene-down-regulates-htert-at-physiological-concentrations-in-breast-cancer-cells-potentially-through-the-inhibition-of-cmyc
#2
Michael Daniel, Trygve O Tollefsbol
Human telomerase reverse transcriptase (hTERT) encodes the catalytic subunit of telomerase, which has been shown to be upregulated in many cancers. Pterostilbene is a naturally occurring stilbenoid and phytoalexin found primarily in blueberries that exhibits antioxidant activity and inhibits the growth of various cancer cell types. Therefore, the aim of this study was to determine whether treatment with pterostilbene, at physiologically achievable concentrations, can inhibit the proliferation of breast cancer cells and down-regulate the expression of hTERT...
November 10, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29108569/a-genome-inspired-reverse-selection-approach-to-aptamer-discovery
#3
Christina M Albanese, Suttipong Suttapitugsakul, Shruthi Perati, Linda B McGown
Limitations of Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and related methods that depend upon combinatorial oligonucleotide libraries have hindered progress in this area. Our laboratory has introduced a new approach to aptamer discovery that uses oligonucleotides with sequences drawn from the human genome to capture proteins from biological samples. Specifically, we have focused on capture of proteins in nuclear extracts from human cell lines using G-quadruplex (G4) forming genomic sequences...
January 15, 2018: Talanta
https://www.readbyqxmd.com/read/29107034/histone-deacetylase-atsrt1-rregulates-metabolic-flux-and-stress-response-in-arabidopsis
#4
Xiaoyun Liu, Wei Wei, Wenjun Zhu, Lufang Su, Zeyang Xiong, Man Zhou, Yu Zheng, Dao-Xiu Zhou
How plant metabolic flux alters gene expression to optimize plant growth and response to stress remains largely unclear. Here, we report that Arabidopsis thaliana NAD(+)-dependent histone deacetylase AtSRT1 negatively regulates plant tolerance to stress and glycolysis but stimulates mitochondrial respiration. We found that AtSRT1 interacts with Arabidopsis cMyc-Binding Protein-1 (AtMBP-1), a transcriptional repressor produced by alternative translation of the cytosolic glycolytic enolase gene LOS2/ENO2. We demonstrated that AtSRT1 could associate with the chromatin of AtMBP-1 targets LOS2/ENO2 and STZ/ZAT10, both of which encode key stress regulators, and reduce the H3K9ac levels at these genes to repress their transcription...
October 26, 2017: Molecular Plant
https://www.readbyqxmd.com/read/29067216/genotyping-tumour-dna-in-cerebrospinal-fluid-and-plasma-of-a-her2-positive-breast-cancer-patient-with-brain-metastases
#5
Giulia Siravegna, Elena Geuna, Benedetta Mussolin, Giovanni Crisafulli, Alice Bartolini, Danilo Galizia, Laura Casorzo, Ivana Sarotto, Maurizio Scaltriti, Anna Sapino, Alberto Bardelli, Filippo Montemurro
BACKGROUND: Central nervous system (CNS) involvement contributes to significant morbidity and mortality in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) and represents a major challenge for clinicians. Liquid biopsy of cerebrospinal fluid (CSF)-derived circulating tumour DNA (ctDNA) harbours clinically relevant genomic alterations in patients with CNS metastases and could be effective in tracking tumour evolution. METHODS: In a HER2-positive mBC patient with brain metastases, we applied droplet digital PCR (ddPCR) and next-generation whole exome sequencing (WES) analysis to measure ctDNA dynamic changes in CSF and plasma collected during treatment...
2017: ESMO Open
https://www.readbyqxmd.com/read/29042999/pien-tze-huang-inhibits-the-proliferation-of-colorectal-cancer-cells-by-increasing-the-expression-of-mir-34c-5p
#6
Yun Wan, Aling Shen, Fei Qi, Jianfeng Chu, Qiaoyan Cai, Thomas Joseph Sferra, Jun Peng, Youqin Chen
MicroRNAs (miRNAs) are small, short endogenous non-coding RNA that act as oncogenes or tumor suppressors, and serve an important role in various human malignant cancers, including colorectal cancer (CRC). Evidence has indicated that miRNAs regulate the expression of various genes associated with human cancer, in particular the miR-34 family. A well-known traditional Chinese formula, Pien Tze Huang (PZH), has a significant clinical effect on CRC. Previous studies have demonstrated that PZH inhibits CRC growth in vitro and in vivo via multiple mechanisms, including the induction of apoptosis, inhibition of cell proliferation and tumor angiogenesis...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29034900/generation-of-ipsc-line-from-patient-with-arrhythmogenic-right-ventricular-cardiomyopathy-carrying-mutations-in-pkp2-gene
#7
Aleksandr Khudiakov, Daria Kostina, Anna Zlotina, Natalia Yany, Alexey Sergushichev, Tatiana Pervunina, Alexey Tomilin, Anna Kostareva, Anna Malashicheva
Human iPSC line was generated from patient-specific adipose tissue-derived mesenchymal multipotent stromal cells carrying two mutations in plakophilin-2 (PKP2) gene using non-integrative reprogramming method. Reprogramming factors OCT4, KLF4, SOX2, CMYC were delivered using Sendai viruses. Pluripotency was confirmed in vitro using immunofluorescence and RT-PCR analysis and in vivo by teratoma assay. The reported iPSC line could be useful tool for in vitro modeling of arrhythmogenic right ventricular cardiomyopathy...
October 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29034897/generation-of-ipsc-line-from-desmin-related-cardiomyopathy-patient-carrying-splice-site-mutation-of-des-gene
#8
Aleksandr Khudiakov, Daria Kostina, Anna Zlotina, Tatiana Nikulina, Alexey Sergushichev, Alexandra Gudkova, Alexey Tomilin, Anna Malashicheva, Anna Kostareva
Human iPSC line was generated from patient-specific adipose tissue-derived mesenchymal multipotent stromal cells carrying desmin (DES) gene heterozygous splice site mutation using non-integrative reprogramming method. Reprogramming factors OCT4, KLF4, SOX2, CMYC were delivered using Sendai viruses. iPSCs were characterized by sequencing, karyotype analysis, STR analysis, immunocytochemistry, RT-PCR and teratoma formation.
October 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28981733/prognostic-factors-for-primary-central-nervous-system-lymphomas-treated-with-high-dose-methotrexate-based-chemo-radiotherapy
#9
Jeunghun Lee, Yukiko Shishido-Hara, Kaori Suzuki, Saki Shimizu, Keiichi Kobayashi, Hiroshi Kamma, Yoshiaki Shiokawa, Motoo Nagane
Background: Primary central nervous system lymphoma (PCNSL) remains an aggressive and refractory tumor despite high-dose methotrexate-based chemo-radiotherapy. Age and performance status have been shown to be important clinical prognostic factors, however others, especially molecular factors, affecting the prognosis are still uncertain. Methods: We investigate clinical, neuroimaging and immunohistochemical data in tissue from 41 PCNSL patients treated primarily with methotrexate-based chemo-radiotherapy and evaluate the influence of potential prognostic factors on clinical outcome as well as correlation among these factors...
October 1, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28974238/cmyc-expression-in-thyroid-follicular-cell-derived-carcinomas-a-role-in-thyroid-tumorigenesis
#10
Hany I Sakr, Deborah J Chute, Christian Nasr, Charles D Sturgis
BACKGROUND: cMYC regulates approximately 15% of human genes and is involved in up to 20% of all human cancers. Reports discussing cMYC protein expression in thyroid carcinomas are limited, with controversies pertaining to cMYC expression patterns noted in the literature. The aims of the current study were to clarify patterns and intensities of cMYC expression in follicular cell-derived thyroid carcinomas across a spectrum of cancer morphologies and disease aggressivities, to correlate cMYC with BRAF(V600E) expression, and to evaluate the potential role of cMYC in progression of well-differentiated thyroid carcinomas into less well-differentiated carcinomas...
October 3, 2017: Diagnostic Pathology
https://www.readbyqxmd.com/read/28972002/direct-comparison-of-cardiac-myosin-binding-protein-c-with-cardiac-troponins-for-the-early-diagnosis-of-acute-myocardial-infarction
#11
MULTICENTER STUDY
Thomas E Kaier, Raphael Twerenbold, Christian Puelacher, Jack Marjot, Nazia Imambaccus, Jasper Boeddinghaus, Thomas Nestelberger, Patrick Badertscher, Zaid Sabti, Maria Rubini Giménez, Karin Wildi, Petra Hillinger, Karin Grimm, Sarah Loeffel, Samyut Shrestha, Dayana Flores Widmer, Janosch Cupa, Nikola Kozhuharov, Òscar Miró, F Javier Martín-Sánchez, Beata Morawiec, Katharina Rentsch, Jens Lohrmann, Wanda Kloos, Stefan Osswald, Tobias Reichlin, Ekkehard Weber, Michael Marber, Christian Mueller
BACKGROUND: Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI. METHODS: Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation...
October 17, 2017: Circulation
https://www.readbyqxmd.com/read/28915556/critical-roles-of-smyd2-mediated-%C3%AE-catenin-methylation-for-nuclear-translocation-and-activation-of-wnt-signaling
#12
Xiaolan Deng, Ryuji Hamamoto, Theodore Vougiouklakis, Rui Wang, Yuichiro Yoshioka, Takehiro Suzuki, Naoshi Dohmae, Yo Matsuo, Jae-Hyun Park, Yusuke Nakamura
Accumulation of β-catenin in the nucleus is a hallmark of activation of the Wnt/β-catenin signaling pathway, which drives development of a large proportion of human cancers. However, the mechanism of β-catenin nuclear translocation has not been well investigated. Here we report biological significance of SMYD2-mediated lysine 133 (K133) methylation of β-catenin on its nuclear translocation. Knockdown of SMYD2 attenuates the nuclear localization of β-catenin protein in human cancer cells. Consequently, transcriptional levels of well-known Wnt-signaling molecules, cMYC and CCND1, are significantly reduced...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881081/a-genetically-inducible-porcine-model-of-intestinal-cancer
#13
Morten M Callesen, Sigrid S Árnadóttir, Iben Lyskjaer, Mai-Britt W Ørntoft, Søren Høyer, Frederik Dagnaes-Hansen, Ying Liu, Rong Li, Henrik Callesen, Mads H Rasmussen, Martin F Berthelsen, Martin K Thomsen, Pawel J Schweiger, Kim B Jensen, Søren Laurberg, Torben F Ørntoft, Jannik E Elverløv-Jakobsen, Claus L Andersen
Transgenic porcine cancer models bring novel possibilities for research. Their physical similarities with humans enable the use of surgical procedures and treatment approaches used for patients, which facilitates clinical translation. Here, we aimed to develop an inducible oncopig model of intestinal cancer. Transgenic (TG) minipigs were generated using somatic cell nuclear transfer by handmade cloning. The pigs encode two TG cassettes: (a) an Flp recombinase-inducible oncogene cassette containing KRAS-G12D, cMYC, SV40LT - which inhibits p53 - and pRB and (b) a 4-hydroxytamoxifen (4-OHT)-inducible Flp recombinase activator cassette controlled by the intestinal epithelium-specific villin promoter...
November 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28875331/implication-of-connexin30-on-the-stemness-of-glioma-connexin30-reverses-the-malignant-phenotype-of-glioma-by-modulating-igf-1r-cd133-and-cmyc
#14
Sankaradoss Arun, Shantha Ravisankar, Arambakkam Janardhanam Vanisree
Gap-junctional intercellular communication (GJIC) plays a major role in the malignant growth of glioma. Although the mechanistic aspects of GJIC have been extensively studied, the role of connexins in the regulation of the malignant behavior of glioma stem cells (GSCs) remains unclear. In our previous studies, we have shown that connexin30 can interfere with the insulin-like growth factor 1 receptor (IGF-1R), which is known for self-renewal and pluripotency. Following our earlier in vitro observation, in this work, we aimed to study the consequence of this influence of Cx30 on IGF-1R by evaluating the marker of GSCs, CD133 and oncoprotein, cMyc...
September 5, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28859475/identification-of-slirp-as-a-g-quadruplex-binding-protein
#15
Preston Williams, Lin Li, Xiaoli Dong, Yinsheng Wang
The guanine quadruplex (G4) structure in DNA is a secondary structure motif that plays important roles in DNA replication, transcriptional regulation, and maintenance of genomic stability. Here, we employed a quantitative mass spectrometry-based approach to profile the interaction proteomes of three well-defined G4 structures derived from the human telomere and the promoters of cMYC and cKIT genes. We identified SLIRP as a novel G4-interacting protein. We also demonstrated that the protein could bind directly with G4 DNA with Kd values in the low nanomolar range and revealed that the robust binding of the protein toward G4 DNA requires its RRM domain...
September 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28830912/mapping-genetic-vulnerabilities-reveals-btk-as-a-novel-therapeutic-target-in-oesophageal-cancer
#16
Irene Yushing Chong, Lauren Aronson, Hanna Bryant, Aditi Gulati, James Campbell, Richard Elliott, Stephen Pettitt, Paul Wilkerson, Maryou B Lambros, Jorge S Reis-Filho, Anisha Ramessur, Michael Davidson, Ian Chau, David Cunningham, Alan Ashworth, Christopher J Lord
OBJECTIVE: Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. DESIGN: To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations...
August 22, 2017: Gut
https://www.readbyqxmd.com/read/28819416/expression-of-cd133-in-endometrial-cancer-cells-and-its-implications
#17
Dah-Ching Ding, Hwan-Wun Liu, Yu-Hsun Chang, Tang-Yuan Chu
Cancer stem cells are an attractive therapeutic target for cancer. The present study examined stem cell characteristics of CD133+ cells isolated from endometrial cancer. Phenotypic characteristics, proliferation, migration, anchorage-independent growth, chemoresistance, gene expression profile and tumorigenicity of CD133+ tumor cells were assessed. Primary tumor exhibited immunoreactivity for CD133. Endometrial CD133+ tumor cells enhanced proliferation rate, colony formation, chemotaxis migration ability, and chemoresistance to cisplatin, paclitaxel, and doxorubicin than CD133- cells...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28815764/aligning-digital-cd8-scoring-and-targeted-next-generation-sequencing-with-pd-l1-expression-a-pragmatic-approach-in-early-stage-squamous-cell-lung-carcinoma
#18
Esther Conde, Alejandra Caminoa, Carolina Dominguez, Antonio Calles, Stefan Walter, Barbara Angulo, Elena Sánchez, Marta Alonso, Luis Jimenez, Luis Madrigal, Florentino Hernando, Julian Sanz-Ortega, Beatriz Jimenez, Pilar Garrido, Luis Paz-Ares, Javier de Castro, Susana Hernandez, Fernando Lopez-Rios
AIMS: To study PD-L1 expression, tumour-infiltrating T lymphocytes (TILs) and the molecular context in patients with early-stage squamous cell lung carcinomas (SCCs). METHODS AND RESULTS: The study included samples from 40 patients (discovery cohort) and 29 patients (validation cohort) diagnosed with early-stage SCC. PD-L1 immunohistochemistry (IHC) was performed with three commercially available clones (E1L3N, SP263 and SP142). CD8(+) TILs were scored with a digital algorithm...
August 16, 2017: Histopathology
https://www.readbyqxmd.com/read/28813671/oct4-and-sox2-work-as-transcriptional-activators-in-reprogramming-human-fibroblasts
#19
Santosh Narayan, Gene Bryant, Shivangi Shah, Georgina Berrozpe, Mark Ptashne
SOX2 and OCT4, in conjunction with KLF4 and cMYC, are sufficient to reprogram human fibroblasts to induced pluripotent stem cells (iPSCs), but it is unclear if they function as transcriptional activators or as repressors. We now show that, like OCT4, SOX2 functions as a transcriptional activator. We substituted SOX2-VP16 (a strong activator) for wild-type (WT) SOX2, and we saw an increase in the efficiency and rate of reprogramming, whereas the SOX2-HP1 fusion (a strong repressor) eliminated reprogramming...
August 15, 2017: Cell Reports
https://www.readbyqxmd.com/read/28792659/molecular-alterations-in-pediatric-brainstem-gliomas
#20
Mikaela Porkholm, Anna Raunio, Reetta Vainionpää, Tarja Salonen, Juha Hernesniemi, Leena Valanne, Jarno Satopää, Atte Karppinen, Minna Oinas, Olli Tynninen, Virve Pentikäinen, Sanna-Maria Kivivuori
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group...
August 9, 2017: Pediatric Blood & Cancer
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