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https://www.readbyqxmd.com/read/29440175/pan-cancer-molecular-classes-transcending-tumor-lineage-across-32-cancer-types-multiple-data-platforms-and-over-10-000-cases
#1
Chad J Creighton, Fengju Chen, Yiqun Zhang, Don L Gibbons, Benjamin Deneen, David Kwiatkowski, Michael Ittmann
PURPOSE: The Cancer Genome Atlas data resources represent an opportunity to explore commonalities across cancer types involving multiple molecular levels, but tumor lineage and histology can represent a barrier in moving beyond differences related to cancer type. EXPERIMENTAL DESIGN: On the basis of gene expression data, we classified 10224 cancers, representing 32 major types, into ten molecular-based "classes."  Molecular patterns representing tissue or histologic dominant effects were first removed computationally, with the resulting classes representing emergent themes across tumor lineages...
February 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29438694/allele-specific-chromatin-recruitment-and-therapeutic-vulnerabilities-of-esr1-activating-mutations
#2
Rinath Jeselsohn, Johann S Bergholz, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Agostina Nardone, Tengfei Xiao, Wei Li, Xintao Qiu, Gilles Buchwalter, Ariel Feiglin, Kayley Abell-Hart, Teng Fei, Prakash Rao, Henry Long, Nicholas Kwiatkowski, Tinghu Zhang, Nathanael Gray, Diane Melchers, Rene Houtman, X Shirley Liu, Ofir Cohen, Nikhil Wagle, Eric P Winer, Jean Zhao, Myles Brown
Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER + ) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype...
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29408204/high-mitf-expression-is-associated-with-super-enhancers-and-suppressed-by-cdk7-inhibition-in-melanoma
#3
Philip Eliades, Brian J Abraham, Zhenyu Ji, David M Miller, Camilla L Christensen, Nicholas Kwiatkowski, Raj Kumar, Ching Ni Njauw, Michael Taylor, Benchun Miao, Tinghu Zhang, Kwok-Kin Wong, Nathanael S Gray, Richard A Young, Hensin Tsao
Cutaneous melanoma is an aggressive tumor which accounts for most of the skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes that specify melanocyte identity such as MITF - a phenomenon known in melanoma biology as "lineage dependency." MITF overexpression is occasionally explained by gene amplification, but here we demonstrate that "super-enhancers" are also important determinants of MITF overexpression in some melanoma cell lines and tumors...
February 2, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29398453/updated-molecular-testing-guideline-for-the-selection-of-lung-cancer-patients-for-treatment-with-targeted-tyrosine-kinase-inhibitors-guideline-from-the-college-of-american-pathologists-the-international-association-for-the-study-of-lung-cancer-and-the-association
#4
Neal I Lindeman, Philip T Cagle, Dara L Aisner, Maria E Arcila, Mary Beth Beasley, Eric Bernicker, Carol Colasacco, Sanja Dacic, Fred R Hirsch, Keith Kerr, David J Kwiatkowski, Marc Ladanyi, Jan A Nowak, Lynette Sholl, Robyn Temple-Smolkin, Benjamin Solomon, Lesley H Souter, Erik Thunnissen, Ming S Tsao, Christina B Ventura, Murry W Wynes, Yasushi Yatabe
CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update...
January 23, 2018: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29398391/origins-of-the-current-outbreak-of-multidrug-resistant-malaria-in-southeast-asia-a-retrospective-genetic-study
#5
Roberto Amato, Richard D Pearson, Jacob Almagro-Garcia, Chanaki Amaratunga, Pharath Lim, Seila Suon, Sokunthea Sreng, Eleanor Drury, Jim Stalker, Olivo Miotto, Rick M Fairhurst, Dominic P Kwiatkowski
BACKGROUND: Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin-piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports. METHODS: We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013...
February 1, 2018: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/29396253/updated-molecular-testing-guideline-for-the%C3%A2-selection-of-lung-cancer-patients-for-treatment-with-targeted-tyrosine-kinase-inhibitors-guideline-from-the-college-of-american-pathologists-the%C3%A2-international-association-for-the-study-of-lung-cancer-and-the%C3%A2-association
#6
Neal I Lindeman, Philip T Cagle, Dara L Aisner, Maria E Arcila, Mary Beth Beasley, Eric Bernicker, Carol Colasacco, Sanja Dacic, Fred R Hirsch, Keith Kerr, David J Kwiatkowski, Marc Ladanyi, Jan A Nowak, Lynette Sholl, Robyn Temple-Smolkin, Benjamin Solomon, Lesley H Souter, Erik Thunnissen, Ming S Tsao, Christina B Ventura, Murry W Wynes, Yasushi Yatabe
CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update...
January 23, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29394917/analysis-of-tumour-infiltrating-lymphocytes-reveals-two-new-biologically-different-subgroups-of-breast-ductal-carcinoma-in-situ
#7
Marie Beguinot, Marie-Melanie Dauplat, Fabrice Kwiatkowski, Guillaume Lebouedec, Lucie Tixier, Christophe Pomel, Frederique Penault-Llorca, Nina Radosevic-Robin
BACKGROUND: Tumour-infiltrating lymphocytes (TILs) have been demonstrated to significantly influence prognosis and response to therapy of invasive breast cancer (IBC). Thus, it has been suggested that TIL density or/and immunophenotype could serve as biomarkers for selection of IBC patients for immunotherapy. However, much less is known about significance of TILs in breast ductal carcinoma in situ (DCIS). METHODS: We retrospectively investigated TIL density and immunophenotype in 96 pure DCIS and 35 microinvasive carcinomas (miCa)...
February 3, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29374710/decreased-expression-of-satb2-associates-with-tumor-growth-and-predicts-worse-outcome-in-patients-with-clear-cell-renal-cell-carcinoma
#8
Agnieszka Sliwinska-Jewsiewicka, Anna E Kowalczyk, Bartlomiej E Krazinski, Janusz Godlewski, Przemyslaw Kwiatkowski, Jolanta Kiewisz, Jedrzej Grzegrzolka, Piotr Dziegiel, Zbigniew Kmiec
BACKGROUND/AIM: SATB2 (special AT-rich sequence-binding protein 2) is a DNA-binding protein that is involved in transcriptional regulation and chromatin remodeling. SATB2 protein has been described as a promising novel marker in several human cancers. PATIENTS AND METHODS: This study compared SATB2 expression in tumor and matched unchanged renal tissues collected from 57 patients with clear cell renal cell carcinoma (ccRCC). SATB2 mRNA levels were determined by quantitative polymerase chain reaction, while SATB2 protein expression was estimated by immunohistochemistry...
February 2018: Anticancer Research
https://www.readbyqxmd.com/read/29374585/unrelated-donor-transplantation-in-children-with-thalassemia-using-reduced-intensity-conditioning-the-urth-trial
#9
Shalini Shenoy, Mark C Walters, Alex Ngwube, Sandeep Soni, David Jacobsohn, Sonali Chaudhury, Michael Grimley, Kawah Chan, Ann Haight, Kimberley A Kasow, Suhag Parikh, Martin Andreansky, Jim Connelly, David Delgado, Kamar Godder, Gregory Hale, Michael Nieder, Michael A Pulsipher, Felicia Trachtenberg, Ellis Neufeld, Janet L Kwiatkowski, Alexis A Thompson
Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial, we investigated the efficacy of reduced intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children (1-17 years), received marrow or cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 (range, 10-25) and 24 (range, 18-49) days; platelet engraftment was 23 (range, 12-46) and 50 (range, 31-234) days after marrow and UCB respectively...
January 25, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29369625/high-throughput-assessment-of-structural-continuity-in-biologics
#10
Caterina Musetti, Mark Bean, Geoffrey Quinque, Christopher Kwiatkowski, Lawrence Szewczuk, John Baldoni, Matthew Allen Zajac
We demonstrate a high-throughput chemoprinting platform that confirms the consistency in the higher-order structure of protein biologics and is sensitive enough to detect single-point mutations. This method addresses the quality and consistency of the tertiary and quaternary structure of biologic drug products, which is arguably the most important, yet rarely examined parameter. The method described uses specific small molecule ligands as molecular probes to assess protein structure. Each library of probe molecules provides a "fingerprint" when taken holistically...
January 25, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29358035/ews-fli-confers-tumor-cell-synthetic-lethality-to-cdk12-inhibition-in-ewing-sarcoma
#11
Amanda Balboni Iniguez, Björn Stolte, Emily Jue Wang, Amy Saur Conway, Gabriela Alexe, Neekesh V Dharia, Nicholas Kwiatkowski, Tinghu Zhang, Brian J Abraham, Jaume Mora, Peter Kalev, Alan Leggett, Dipanjan Chowdhury, Cyril H Benes, Richard A Young, Nathanael S Gray, Kimberly Stegmaier
Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression...
January 17, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29355391/updated-molecular-testing-guideline-for-the-selection-of-lung-cancer-patients-for-treatment-with-targeted-tyrosine-kinase-inhibitors-guideline-from-the-college-of-american-pathologists-the-international-association-for-the-study-of-lung-cancer-and-the-association
#12
Neal I Lindeman, Philip T Cagle, Dara L Aisner, Maria E Arcila, Mary Beth Beasley, Eric Bernicker, Carol Colasacco, Sanja Dacic, Fred R Hirsch, Keith Kerr, David J Kwiatkowski, Marc Ladanyi, Jan A Nowak, Lynette Sholl, Robyn Temple-Smolkin, Benjamin Solomon, Lesley H Souter, Erik Thunnissen, Ming S Tsao, Christina B Ventura, Murry W Wynes, Yasushi Yatabe
CONTEXT: - In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: - To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update...
January 22, 2018: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/29347480/effect-of-mobility-ratio-on-interaction-between-the-fingers-in-unstable-growth-processes
#13
Agnieszka Budek, Kamil Kwiatkowski, Piotr Szymczak
We investigate interactions between thin fingers formed as a result of an instability of an advancing front in growth processes. We show that the fingers can both attract and repel each other, depending on their lengths and the mobility ratio between the invading and displaced phase. To understand the origin of these interactions we introduce a simple resistor model of the fingers. The predictions of the model are then compared to the numerical simulations of two unstable growth processes: dissolution of partially cemented rock fracture and viscous fingering in a regular network of channels...
October 2017: Physical Review. E
https://www.readbyqxmd.com/read/29340031/analyzing-the-influence-of-kinase-inhibitors-on-dna-repair-by-differential-proteomics-of-chromatin-interacting-proteins-and-nuclear-phospho-proteins
#14
Lisa Gleißner, Marcel Kwiatkowski, Laura Myllynen, Pascal Steffen, Cordula Petersen, Kai Rothkamm, Hartmut Schlüter, Malte Kriegs
The combination of radiotherapy and pharmacological inhibition of cellular signal transduction pathways offers promising strategies for enhanced cancer cell inactivation. However, the molecular effects of kinase inhibitors especially on DNA damage detection and repair after X-irradiation have to be understood to facilitate the development of efficient and personalized treatment regimens. Therefore, we applied differential proteomics for analyzing inhibitor-induced changes in either chromatin-bound or phosphorylated nuclear proteins...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29319328/deferasirox-decreases-busulfan-clearance
#15
Jennifer Kwiatkowski, Ulrich Duffner, Aly Abdel-Mageed
No abstract text is available yet for this article.
January 1, 2018: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/29289701/dopamine-transporter-knockdown-mice-in-the-behavioral-pattern-monitor-a-robust-reproducible-model-for-mania-relevant-behaviors
#16
Molly A Kwiatkowski, Gerhard Hellemann, Catherine A Sugar, Zackary A Cope, Arpi Minassian, William Perry, Mark A Geyer, Jared W Young
Efforts to replicate results from both basic and clinical models have highlighted problems with reproducibility in science. In psychiatry, reproducibility issues are compounded because the complex behavioral syndromes make many disorders challenging to model. We develop translatable tasks that quantitatively measure psychiatry-relevant behaviors across species. The behavioral pattern monitor (BPM) was designed to analyze exploratory behaviors, which are altered in patients with bipolar disorder (BD), especially during mania episodes...
December 28, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/29289186/picosecond-precision-multichannel-autonomous-time-and-frequency-counter
#17
R Szplet, P Kwiatkowski, K Różyc, Z Jachna, T Sondej
This paper presents the design, implementation, and test results of a multichannel time interval and frequency counter developed as a desktop instrument. The counter contains four main functional modules for (1) performing precise measurements, (2) controlling and fast data processing, (3) low-noise power suppling, and (4) supplying a stable reference clock (optional rubidium standard). A fundamental for the counter, the time interval measurement is based on time stamping combined with a period counting and in-period two-stage time interpolation that allows us to achieve wide measurement range (above 1 h), high precision (even better than 4...
December 2017: Review of Scientific Instruments
https://www.readbyqxmd.com/read/29281825/somatic-mutations-activating-the-mtor-pathway-in-dorsal-telencephalic-progenitors-cause-a-continuum-of-cortical-dysplasias
#18
Alissa M D'Gama, Mollie B Woodworth, Amer A Hossain, Sara Bizzotto, Nicole E Hatem, Christopher M LaCoursiere, Imad Najm, Zhong Ying, Edward Yang, A James Barkovich, David J Kwiatkowski, Harry V Vinters, Joseph R Madsen, Gary W Mathern, Ingmar Blümcke, Annapurna Poduri, Christopher A Walsh
Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29276047/overcoming-resistance-to-the-thz-series-of-covalent-transcriptional-cdk-inhibitors
#19
Yang Gao, Tinghu Zhang, Hideki Terai, Scott B Ficarro, Nicholas Kwiatkowski, Ming-Feng Hao, Bandana Sharma, Camilla L Christensen, Edmond Chipumuro, Kwok-Kin Wong, Jarrod A Marto, Peter S Hammerman, Nathanael S Gray, Rani E George
Irreversible inhibition of transcriptional cyclin-dependent kinases (CDKs) provides a therapeutic strategy for cancers that rely on aberrant transcription; however, lack of understanding of resistance mechanisms to these agents will likely impede their clinical evolution. Here, we demonstrate upregulation of multidrug transporters ABCB1 and ABCG2 as a major mode of resistance to THZ1, a covalent inhibitor of CDKs 7, 12, and 13 in neuroblastoma and lung cancer. To counter this obstacle, we developed a CDK inhibitor, E9, that is not a substrate for ABC transporters, and by selecting for resistance, determined that it exerts its cytotoxic effects through covalent modification of cysteine 1039 of CDK12...
December 15, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29259014/er-stress-signaling-promotes-the-survival-of-cancer-persister-cells-tolerant-to-egfr-tyrosine-kinase-inhibitors
#20
Hideki Terai, Shunsuke Kitajima, Danielle S Potter, Yusuke Matsui, Laura Gutierrez Quiceno, Ting Chen, Tae-Jung Kim, Maria Rusan, Tran C Thai, Federica Piccioni, Katherine A Donovan, Nicholas Kwiatkowski, Kunihiko Hinohara, Guo Wei, Nathanael S Gray, Eric S Fischer, Kwok-Kin Wong, Teppei Shimamura, Anthony Letai, Peter S Hammerman, David A Barbie
An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells which survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways...
December 19, 2017: Cancer Research
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