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https://www.readbyqxmd.com/read/29143233/etoposide-upregulates-survival-favoring-sphingosine-1-phosphate-in-etoposide-resistant-retinoblastoma-cells
#1
Vinodh Kakkassery, S Skosyrski, A Lüth, B Kleuser, M van der Giet, R Tate, J Reinhard, A Faissner, S C Joachim, N Kociok
Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry...
November 15, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/29137657/p53-aberrations-in-low-grade-endometrioid-carcinoma-of-the-endometrium-with-nodal-metastases-possible-insights-on-pathogenesis-discerned-from-immunohistochemistry
#2
Oluwole Fadare, Vinita Parkash
BACKGROUND: TP53 mutations are rarely identified in low grade endometrioid carcinoma of the endometrium, and their pathogenic significance in such tumors is evidenced by the fact that TP53 aberrations have been associated with reduced recurrence-free survival in this subset of tumors. However, TP53 aberrations may not always represent a driving molecular event in a given endometrial cancer with a mutation. In this case study, the immunophenotype of a distinctive low grade endometrioid adenocarcinoma with an unusual pattern of lymph node metastases is used to explore the possible roles for underlying TP53-related molecular events in its pathogenesis...
November 14, 2017: Diagnostic Pathology
https://www.readbyqxmd.com/read/29137288/elevated-timp-1-expression-is-associated-with-a-prometastatic-phenotype-disease-relapse-and-poor-survival-in-neuroblastoma
#3
Pritha Paul, Eric J Rellinger, Jingbo Qiao, Sora Lee, Natasha Volny, Chandrasekhar Padmanabhan, Carmelle V Romain, Bret Mobley, Hernan Correa, Dai H Chung
Approximately two-thirds of patients with neuroblastoma are found to have metastatic disease at time of diagnosis with frequent skeletal, lymph node, central nervous system, and liver involvement. Using a serial in vivo splenic injection model, we have isolated an aggressive subclone (BE(2)-C/LM2) from MYCN-amplified neuroblastomas that demonstrate an enhanced propensity to develop metastatic liver lesions. BE(2)-C/LM2 subclone cells demonstrate increased adherent, soft agar colony and tumorsphere growth in vitro...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29132144/a-neoantigen-fitness-model-predicts-tumour-response-to-checkpoint-blockade-immunotherapy
#4
Marta Łuksza, Nadeem Riaz, Vladimir Makarov, Vinod P Balachandran, Matthew D Hellmann, Alexander Solovyov, Naiyer A Rizvi, Taha Merghoub, Arnold J Levine, Timothy A Chan, Jedd D Wolchok, Benjamin D Greenbaum
Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells...
November 8, 2017: Nature
https://www.readbyqxmd.com/read/29130628/characterization-of-genetic-intratumor-heterogeneity-in-colorectal-cancer-and-matching-patient-derived-spheroid-cultures
#5
Sigrid Salling Árnadóttir, Maria Jeppesen, Philippe Lamy, Jesper Bertram Bramsen, Iver Nordentoft, Michael Knudsen, Søren Vang, Mogens Rørbaek Madsen, Ole Thastrup, Jacob Thastrup, Claus Lindbjerg Andersen
Patient-derived in vitro cultures of colorectal cancer (CRC) may help guide treatment strategies prior to patient treatment. However, most previous studies have been performed on a single biopsy per tumor. The purpose of this study was to analyze multiple spatially distinct biopsies from CRCs and see how well intratumor heterogeneity (ITH) was recapitulated in matching patient-derived spheroids. Three to five biopsies were collected from six CRC tumors. Each biopsy was split in two; one half was used for spheroid culturing, the other half was used for DNA and RNA purification...
November 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29122777/genetic-predictors-of-response-to-systemic-therapy-in-esophagogastric-cancer
#6
Yelena Y Janjigian, Francisco Sanchez-Vega, Philip Jonsson, Walid K Chatila, Jaclyn F Hechtman, Geoffrey Y Ku, Jamie C Riches, Yaelle Tuvy, Ritika Kundra, Nancy Bouvier, Efsevia Vakiani, Jianjiong Gao, Zachary J Heins, Benjamin E Gross, David P Kelsen, Liying Zhang, Vivian E Strong, Mark Schattner, Hans Gerdes, Daniel G Coit, Manjit Bains, Zsofia K Stadler, Valerie W Rusch, David R Jones, Daniela Molena, Jinru Shia, Mark E Robson, Marinela Capanu, Sumit Middha, Ahmet Zehir, David M Hyman, Maurizio Scaltriti, Marc Ladanyi, Neal Rosen, David H Ilson, Michael F Berger, Laura Tang, Barry S Taylor, David B Solit, Nikolaus Schultz
The incidence of esophagogastric cancer is rapidly rising but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of metastatic esophagogastric cancer patients. There was no association between HRD defects and response to platinum-based chemotherapy. Patients with MSI-H tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy...
November 9, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29117356/spatio-temporal-genomic-heterogeneity-phylogeny-and-metastatic-evolution-in-salivary-adenoid-cystic-carcinoma
#7
Bin Liu, Yoshitsugu Mitani, Xiayu Rao, Mark Zafereo, Jianjun Zhang, Jianhua Zhang, P Andrew Futreal, Guillermina Lozano, Adel K El-Naggar
Background: Adenoid cystic carcinoma (ACC), an uncommon and indolent salivary gland malignancy, is characterized by varied morphologic and clinical manifestations. Molecular genetic studies of ACC identified certain structural and mutational alterations that may play a driver role in tumor development. The evolution and regional consistency of these events in ACC development progression are uncertain. Methods: To investigate the spatial and temporal clonal landscape of ACC, whole-genome sequencing and variant analyses were performed on 34 regionally sampled primary tumors and their concurrent and metachronous metastatic deposits from eight patients...
October 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29117265/genomic-sequencing-identifies-a-few-mutations-driving-the-independent-origin-of-primary-liver-tumors-in-a-chronic-hepatitis-murine-model
#8
Zuyu Yang, Mingming Jia, Guojing Liu, Huaining Hao, Li Chen, Guanghao Li, Sixue Liu, Yawei Li, Chung-I Wu, Xuemei Lu, Shengdian Wang
With the development of high-throughput genomic analysis, sequencing a mouse primary cancer model provides a new opportunity to understand fundamental mechanisms of tumorigenesis and progression. Here, we characterized the genomic variations in a hepatitis-related primary hepatocellular carcinoma (HCC) mouse model. A total of 12 tumor sections and four adjacent non-tumor tissues from four mice were used for whole exome and/or whole genome sequencing and validation of genotyping. The functions of the mutated genes in tumorigenesis were studied by analyzing their mutation frequency and expression in clinical HCC samples...
2017: PloS One
https://www.readbyqxmd.com/read/29115020/glycosylphosphatidylinositol-gpi-anchored-protein-deficiency-serves-as-a-reliable-reporter-of-pig-a-gene-mutation-support-from-an-in-vitro-assay-based-on-l5178y-tk-cells-and-the-cd90-2-antigen
#9
Jeffrey C Bemis, Svetlana L Avlasevich, Carson Labash, Page McKinzie, Javier Revollo, Vasily N Dobrovolsky, Stephen D Dertinger
Lack of cell surface glycosylphosphatidylinositol (GPI)-anchored protein(s) has been used as a reporter of Pig-a gene mutation in several model systems. As an extension of this work, our laboratory initiated development of an in vitro mutation assay based on the flow cytometric assessment of CD90.2 expression on the cell surface of the mouse lymphoma cell line L5178Y/Tk(+/-) . Cells were exposed to mutagenic and nonmutagenic compounds for 24 hr followed by washout and incubation for an additional 7 days. Following this mutant manifestation time, cells were labeled with fluorescent antibodies against CD90...
November 8, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/29112206/intratumoral-heterogeneity-and-clonal-evolution-in-blood-malignancies-and-solid-tumors
#10
Ignacio Varela, Pablo Menendez, Alejandra Sanjuan-Pla
This meeting held at the University of Barcelona in March 2017, brought together scientists and clinicians worldwide to discuss current and future clinico-biological implications of intratumoral heterogeneity (ITH) and subclonal evolution in cancer diagnosis, patient stratification, and treatment resistance in diagnosis, treatment and follow-up. There was consensus that both longitudinal and tumor multi-region studies in matched samples are needed to better understand the dynamics of ITH. The contribution of the epigenome and microenvironment to ITH and subclone evolution remains understudied...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29110262/mutational-diversity-of-lung-cancer-and-associated-lymph-nodes-an-exploratory-prospective-study-of-4-resected-ciiia-n2
#11
Antoine Legras, Hélène Roussel, Giuseppe Mangiameli, Alex Arame, Bertrand Grand, Ciprian Pricopi, Alain Badia, Laure Gibault, Cécile Badoual, Elizabeth Fabre, Pierre Laurent-Puig, Hélène Blons, Françoise Le Pimpec-Barthes
Mutational heterogeneity could explain different metastatic patterns among IIIA-N2 lung cancer and influence prognosis. The identification of subclonal mutations using deep sequencing to evaluate the degree of molecular heterogeneity may improve IIIA-N2 classification. The aim of this prospective study was to assess mutational and immunohistochemical characteristics in primary tumours and involved lymph nodes (LN) in operated patients. Four patients operated for primary lung carcinoma and unisite N2 mediastinal involvement were consecutively selected...
November 6, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/29109480/detection-of-subclonal-l1-transductions-in-colorectal-cancer-by-long-distance-inverse-pcr-and-nanopore-sequencing
#12
Barun Pradhan, Tatiana Cajuso, Riku Katainen, Päivi Sulo, Tomas Tanskanen, Outi Kilpivaara, Esa Pitkänen, Lauri A Aaltonen, Liisa Kauppi, Kimmo Palin
Long interspersed nuclear elements-1 (L1s) are a large family of retrotransposons. Retrotransposons are repetitive sequences that are capable of autonomous mobility via a copy-and-paste mechanism. In most copy events, only the L1 sequence is inserted, however, they can also mobilize the flanking non-repetitive region by a process known as 3' transduction. L1 insertions can contribute to genome plasticity and cause potentially tumorigenic genomic instability. However, detecting the activity of a particular source L1 and identifying new insertions stemming from it is a challenging task with current methodological approaches...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29109420/passage-dependent-accumulation-of-somatic-mutations-in-mesenchymal-stromal-cells-during-in-vitro-culture-revealed-by-whole-genome-sequencing
#13
Myungshin Kim, Je-Keun Rhee, Hayoung Choi, Ahlm Kwon, Jiyeon Kim, Gun Dong Lee, Dong Wook Jekarl, Seungok Lee, Yonggoo Kim, Tae-Min Kim
Human mesenchymal stromal cells (MSCs) have served as a major cellular resource for cell-based immunomodulatory and regenerative therapies. However, genomic instability may accumulate during ex vivo expansion of MSCs, thereby increasing the potential of malignant transformation. Here, we performed whole genome sequencing of two peripheral blood-derived MSC lines (MSC1 and MSC2) at various passages (passage 1 [P1] to P9). The majority of single-nucleotide variations (SNVs) occurred in later passages; specifically, 90% and 70% of all SNVs in MSC1 and MSC2 were observed in P9 and P7/P9, respectively...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29107330/allele-specific-hla-loss-and-immune-escape-in-lung-cancer-evolution
#14
Nicholas McGranahan, Rachel Rosenthal, Crispin T Hiley, Andrew J Rowan, Thomas B K Watkins, Gareth A Wilson, Nicolai J Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity...
October 21, 2017: Cell
https://www.readbyqxmd.com/read/29100507/inhibition-of-pi3k-akt-mtor-overcomes-cisplatin-resistance-in-the-triple-negative-breast-cancer-cell-line-hcc38
#15
Katharina Gohr, Alexandra Hamacher, Laura H Engelke, Matthias U Kassack
BACKGROUND: Widely established targeted therapies directed at triple negative breast cancer (TNBC) are missing. Classical chemotherapy remains the systemic treatment option. Cisplatin has been tested in TNBC but bears the disadvantage of resistance development. The purpose of this study was to identify resistance mechanisms in cisplatin-resistant TNBC cell lines and select targeted therapies based on these findings. METHODS: The TNBC cell lines HCC38 and MDA-MB231 were subjected to intermittent cisplatin treatment resulting in the 3...
November 3, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29095550/downregulation-of-cd24-suppresses-bone-metastasis-of-lung-cancer
#16
Hinako Okabe, Katsuhiko Aoki, Satomi Yogosawa, Mitsuru Saito, Keishi Marumo, Kiyotsugu Yoshida
Suppression of bone metastasis can improve patient quality of life. Current drugs for bone metastasis have been shown to prolong progression-free survival but not overall survival; therefore, other potential therapeutic targets for bone metastasis should be investigated. Cell-surface antigens, such as CD24, have been recently shown to be involved in the metastasis of various cancers. However, whether CD24 plays a role in bone metastasis of lung cancer remains unknown. To observe metastasis of lung cancer cells by imaging technology, we introduced a near-infrared fluorescent protein, iRFP720, into a bone-seeking subclone established from lung cancer cells, HARA-B4 cells...
November 2, 2017: Cancer Science
https://www.readbyqxmd.com/read/29093439/combating-subclonal-evolution-of-resistant-cancer-phenotypes
#17
Samuel W Brady, Jasmine A McQuerry, Yi Qiao, Stephen R Piccolo, Gajendra Shrestha, David F Jenkins, Ryan M Layer, Brent S Pedersen, Ryan H Miller, Amanda Esch, Sara R Selitsky, Joel S Parker, Layla A Anderson, Brian K Dalley, Rachel E Factor, Chakravarthy B Reddy, Jonathan P Boltax, Dean Y Li, Philip J Moos, Joe W Gray, Laura M Heiser, Saundra S Buys, Adam L Cohen, W Evan Johnson, Aaron R Quinlan, Gabor Marth, Theresa L Werner, Andrea H Bild
Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance...
November 1, 2017: Nature Communications
https://www.readbyqxmd.com/read/29090521/single-cell-whole-exome-and-targeted-sequencing-in-npm1-flt3-positive-pediatric-acute-myeloid-leukemia
#18
Christiane Walter, Christian Pozzorini, Katarina Reinhardt, Robert Geffers, Zhenyu Xu, Dirk Reinhardt, Nils von Neuhoff, Helmut Hanenberg
BACKGROUND: The small portion of leukemic stem cells (LSCs) in acute myeloid leukemia (AML) present in children and adolescents is often masked by the high background of AML blasts and normal hematopoietic cells. The aim of the current study was to establish a simple workflow for reliable genetic analysis of single LSC-enriched blasts from pediatric patients. PROCEDURE: For three AMLs with mutations in nucleophosmin 1 and/or fms-like tyrosine kinase 3, we performed whole genome amplification on sorted single-cell DNA followed by whole exome sequencing (WES)...
November 1, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29079199/chd8short-a-naturally-occurring-truncated-form-of-a-chromatin-remodeler-lacking-the-helicase-domain-is-a-potent-transcriptional-coregulator
#19
Gary R Kunkel, Jessica A Tracy, Frank L Jalufka, Arne C Lekven
Chromodomain-Helicase-DNA binding protein 8 (CHD8) is a member of a large family of eukaryotic ATP-dependent chromatin remodeling complexes. Loss of function alleles of human chd8 are correlated with autism spectrum disorder. The CHD subfamily members contain a tandem pair of chromodomains that are adjacent to a centrally located Snf2-like helicase domain. An alternatively spliced variant mRNA of CHD8 was identified years ago in mammals that encode a truncated form of the protein, called Duplin, that lacks the helicase domain and everything else in the carboxyl direction...
October 24, 2017: Gene
https://www.readbyqxmd.com/read/29078205/intratumor-and-intertumor-heterogeneity-in-melanoma
#20
REVIEW
Tomasz M Grzywa, Wiktor Paskal, Paweł K Włodarski
Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment...
October 24, 2017: Translational Oncology
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