المؤلفون: Lisa Uechi, Swetha Vasudevan, Daniela Vilenski, Sergio Branciamore, David Frankhouser, Denis O’Meally, Soheil Meshinchi, Guido Marcucci, Ya-Huei Kuo, Russell Rockne, Nataly Kravchenko-Balasha

المصدر: npj Systems Biology and Applications, Vol 10, Iss 1, Pp 1-10 (2024)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Abstract Acute myeloid leukemia (AML) is prevalent in both adult and pediatric patients. Despite advances in patient categorization, the heterogeneity of AML remains a challenge. Recent studies have explored the use of gene expression data to enhance AML diagnosis and prognosis, however, alternative approaches rooted in physics and chemistry may provide another level of insight into AML transformation. Utilizing publicly available databases, we analyze 884 human and mouse blood and bone marrow samples. We employ a personalized medicine strategy, combining state-transition theory and surprisal analysis, to assess the RNA transcriptome of individual patients. The transcriptome is transformed into physical parameters that represent each sample’s steady state and the free energy change (FEC) from that steady state, which is the state with the lowest free energy. We found the transcriptome steady state was invariant across normal and AML samples. FEC, representing active molecular processes, varied significantly between samples and was used to create patient-specific barcodes to characterize the biology of the disease. We discovered that AML samples that were in a transition state had the highest FEC. This disease state may be characterized as the most unstable and hence the most therapeutically targetable since a change in free energy is a thermodynamic requirement for disease progression. We also found that distinct sets of ongoing processes may be at the root of otherwise similar clinical phenotypes, implying that our integrated analysis of transcriptome profiles may facilitate a personalized medicine approach to cure AML and restore a steady state in each patient.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2056-7189Test

الوصول الحر: https://doaj.org/article/a23d4049946443e3bb7e7c33fa68dc28Test

المؤلفون: Bin Zhang, Dandan Zhao, Fang Chen, David Frankhouser, Huafeng Wang, Khyatiben V. Pathak, Lei Dong, Anakaren Torres, Krystine Garcia-Mansfield, Yi Zhang, Dinh Hoa Hoang, Min-Hsuan Chen, Shu Tao, Hyejin Cho, Yong Liang, Danilo Perrotti, Sergio Branciamore, Russell Rockne, Xiwei Wu, Lucy Ghoda, Ling Li, Jie Jin, Jianjun Chen, Jianhua Yu, Michael A. Caligiuri, Ya-Huei Kuo, Mark Boldin, Rui Su, Piotr Swiderski, Marcin Kortylewski, Patrick Pirrotte, Le Xuan Truong Nguyen, Guido Marcucci

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-21 (2023)

مصطلحات موضوعية: Science

الوصف: Abstract The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38− blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142 −/− BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142 +/+ BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142 −/− BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of “bulk” and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142 −/− BCR-ABL mice and patient-derived xenografts.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/883dc5faaf3c4abe8121ce71d3dc31ceTest

المؤلفون: Kavitha Mukund, Jackelyn A. Alva-Ornelas, Adam L. Maddox, Divya Murali, Darya Veraksa, Andras Saftics, Jerneja Tomsic, David Frankhouser, Meagan Razo, Tijana Jovanovic-Talisman, Victoria L. Seewaldt, Shankar Subramaniam

المصدر: Cancers, Vol 16, Iss 3, p 553 (2024)

مصطلحات موضوعية: HER2+, breast cancer, qSMLM, multiomics, trastuzumab resistance, endogenous ligands, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/16/3/553Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/ec46e4f922164f8da81ba8718909b339Test

المؤلفون: Reuben Franklin, Yiming Guo, Shiyang He, Meijuan Chen, Fei Ji, Xinyue Zhou, David Frankhouser, Brian T. Do, Carmen Chiem, Mihyun Jang, M. Andres Blanco, Matthew G. Vander Heiden, Russell C. Rockne, Maria Ninova, David B. Sykes, Konrad Hochedlinger, Rui Lu, Ruslan I. Sadreyev, Jernej Murn, Andrew Volk, Sihem Cheloufi

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-17 (2022)

مصطلحات موضوعية: Science

الوصف: Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/92b1277f52324a2d9ee446b86d5f55ddTest

المؤلفون: Maximillian Westphal, David Frankhouser, Carmine Sonzone, Peter G. Shields, Pearlly Yan, Ralf Bundschuh

المصدر: BMC Genomics, Vol 20, Iss S12, Pp 1-10 (2019)

مصطلحات موضوعية: Sample swap, Next generation sequencing data, Identity matching, Biotechnology, TP248.13-248.65, Genetics, QH426-470

الوصف: Abstract Background Inadvertent sample swaps are a real threat to data quality in any medium to large scale omics studies. While matches between samples from the same individual can in principle be identified from a few well characterized single nucleotide polymorphisms (SNPs), omics data types often only provide low to moderate coverage, thus requiring integration of evidence from a large number of SNPs to determine if two samples derive from the same individual or not. Methods We select about six thousand SNPs in the human genome and develop a Bayesian framework that is able to robustly identify sample matches between next generation sequencing data sets. Results We validate our approach on a variety of data sets. Most importantly, we show that our approach can establish identity between different omics data types such as Exome, RNA-Seq, and MethylCap-Seq. We demonstrate how identity detection degrades with sample quality and read coverage, but show that twenty million reads of a fairly low quality RNA-Seq sample are still sufficient for reliable sample identification. Conclusion Our tool, SMASH, is able to identify sample mismatches in next generation sequencing data sets between different sequencing modalities and for low quality sequencing data.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2164Test

الوصول الحر: https://doaj.org/article/07fe8bcd6f2d4e1195e0d10126a435a7Test

المؤلفون: Cai Chen, David Frankhouser, Ralf Bundschuh

المصدر: PLoS Computational Biology, Vol 8, Iss 2, p e1002400 (2012)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: RNA editing describes the process in which individual or short stretches of nucleotides in a messenger or structural RNA are inserted, deleted, or substituted. A high level of RNA editing has been observed in the mitochondrial genome of Physarum polycephalum. The most frequent editing type in Physarum is the insertion of individual Cs. RNA editing is extremely accurate in Physarum; however, little is known about its mechanism. Here, we demonstrate how analyzing two organisms from the Myxomycetes, namely Physarum polycephalum and Didymium iridis, allows us to test hypotheses about the editing mechanism that can not be tested from a single organism alone. First, we show that using the recently determined full transcriptome information of Physarum dramatically improves the accuracy of computational editing site prediction in Didymium. We use this approach to predict genes in the mitochondrial genome of Didymium and identify six new edited genes as well as one new gene that appears unedited. Next we investigate sequence conservation in the vicinity of editing sites between the two organisms in order to identify sites that harbor the information for the location of editing sites based on increased conservation. Our results imply that the information contained within only nine or ten nucleotides on either side of the editing site (a distance previously suggested through experiments) is not enough to locate the editing sites. Finally, we show that the codon position bias in C insertional RNA editing of these two organisms is correlated with the selection pressure on the respective genes thereby directly testing an evolutionary theory on the origin of this codon bias. Beyond revealing interesting properties of insertional RNA editing in Myxomycetes, our work suggests possible approaches to be used when finding sequence motifs for any biological process fails.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3285571?pdf=renderTest; https://doaj.org/toc/1553-734XTest; https://doaj.org/toc/1553-7358Test

الوصول الحر: https://doaj.org/article/d28cb99f06f44ce780dc92e67ada3545Test

المؤلفون: Prativa Sahoo, Xin Yang, Daniel Abler, Davide Maestrini, Vikram Adhikarla, David Frankhouser, Heyrim Cho, Vanessa Machuca, Dongrui Wang, Michael Barish, Margarita Gutova, Sergio Branciamore, Christine E. Brown, Russell C. Rockne

مصطلحات موضوعية: Computational Biology, Biological Mathematics, CAR T-cell therapy, mathematical modelling, antigen density, treatment efficacy, CAR T-cell dose, T-cell exhaustion

الوصف: Data in support of results

العلاقة: https://figshare.com/articles/journal_contribution/Supplementary_data_2_Figs_S8_-_S11_from_Mathematical_deconvolution_of_CAR_T-cell_proliferation_and_exhaustion_from_real-time_killing_assay_data/11450079Test

الإتاحة: https://doi.org/10.6084/m9.figshare.11450079.v1Test
https://figshare.com/articles/journal_contribution/Supplementary_data_2_Figs_S8_-_S11_from_Mathematical_deconvolution_of_CAR_T-cell_proliferation_and_exhaustion_from_real-time_killing_assay_data/11450079Test

المؤلفون: Prativa Sahoo, Xin Yang, Daniel Abler, Davide Maestrini, Vikram Adhikarla, David Frankhouser, Heyrim Cho, Vanessa Machuca, Dongrui Wang, Michael Barish, Margarita Gutova, Sergio Branciamore, Christine E. Brown, Russell C. Rockne

مصطلحات موضوعية: Computational Biology, Biological Mathematics, CAR T-cell therapy, mathematical modelling, antigen density, treatment efficacy, CAR T-cell dose, T-cell exhaustion

الوصف: Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of haematological cancers and is currently being investigated for solid tumours, including high-grade glioma brain tumours. There is a desperate need to quantitatively study the factors that contribute to the efficacy of CAR T-cell therapy in solid tumours. In this work, we use a mathematical model of predator–prey dynamics to explore the kinetics of CAR T-cell killing in glioma: the chimeric antigen receptor T-cell treatment response in GliOma (CARRGO) model. The model includes rates of cancer cell proliferation, CAR T-cell killing, CAR T-cell proliferation and exhaustion, and CAR T-cell persistence. We use patient-derived and engineered cancer cell lines with an in vitro real-time cell analyser to parameterize the CARRGO model. We observe that CAR T-cell dose correlates inversely with the killing rate and correlates directly with the net rate of proliferation and exhaustion. This suggests that at a lower dose of CAR T-cells, individual T-cells kill more cancer cells but become more exhausted when compared with higher doses. Furthermore, the exhaustion rate was observed to increase significantly with tumour growth rate and was dependent on level of antigen expression. The CARRGO model highlights nonlinear dynamics involved in CAR T-cell therapy and provides novel insights into the kinetics of CAR T-cell killing. The model suggests that CAR T-cell treatment may be tailored to individual tumour characteristics including tumour growth rate and antigen level to maximize therapeutic benefit.

العلاقة: https://figshare.com/articles/journal_contribution/Table_S1_from_Mathematical_deconvolution_of_CAR_T-cell_proliferation_and_exhaustion_from_real-time_killing_assay_data/11450058Test

الإتاحة: https://doi.org/10.6084/m9.figshare.11450058.v1Test
https://figshare.com/articles/journal_contribution/Table_S1_from_Mathematical_deconvolution_of_CAR_T-cell_proliferation_and_exhaustion_from_real-time_killing_assay_data/11450058Test

المؤلفون: Zhihua Chen, Yifeng Miao, Shun Yao, Denis O’Meally, David Frankhouser, Biao Tang, MingHui Li, Paul Frankel, Mari Shahmanyan, Yongming Qiu, Russell C Rockne

المصدر: Neuro-Oncology. 24:vii274-vii275

مصطلحات موضوعية: Cancer Research, Oncology, Neurology (clinical)

الوصف: BACKGROUND As a rare subtype of glioblastoma (GBM), the genetic features and outcomes in cystic GBM (cGBM) are largely unknown. This study aimed to evaluate the survival of cystic features, investigate genomic patterns and the immune microenvironment in patients with cGBM. METHODS Gd T1-weighted, T2-weighted, T2-Flair, DWI or ADC images were used to classify cGBM or noncystic GBM (non-cGBM). Clinical information from IvyGAP, EGA databases and Chinese cohort were used for survival analysis. Fresh cystic fluid and residual tumor tissue were collected to evaluate immunological components, pathological and genomic differences between cGBM and non-cGBM. Data from IvyGAP were included to determine difference of molecular feature among substructure. RESULTS 143 cases with cGBM and non-cGBM were screened to compare survival outcomes. Cystic features were to confer a survival benefit. It was an independent prognostic factor irrespective of IDH, MGMT and therapeutic regimen. cGBM patients have a hypomethylation state compared to non-cGBM. Active immune cells such as CD4+, CD8+ T cells were present in the cystic fluid and infiltrated into tumor. 10 cytokines/chemokines were only detected in cystic fluid, 8 cytokines/chemokines increased two-fold in cystic fluid than in peripheral blood serum (PBPs). Much differential methylated position (DMPs), differentially expressed genes (DEGs), Gene Set Enrichment Analysis (GSAE), Functional Epigenetic Modules (FEM) networks and molecular feature of substructural regions were different between cGBM and non-cGBM. CONCLUSION These results imply that cGBM could be a new subtype and has distinctive immune microenvironment which may have potential value correlating with prognosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::fc664f8dbfeebdb43af1c210fb085ed2Test
https://doi.org/10.1093/neuonc/noac209.1061Test

المؤلفون: Biao Tang, Denis O’Meally, Mari Shahmanyan, Zhihua Chen, David Frankhouser, Russell C. Rockne, Shu Yao

المصدر: Neuro Oncol

مصطلحات موضوعية: Interleukin 2, Cancer Research, medicine.medical_treatment, O-6-methylguanine-DNA methyltransferase, Biology, 26th Annual Meeting & Education Day of the Society for Neuro-Oncology, Genome, Cell biology, Cytokine, Oncology, CpG site, DNA methylation, Gene expression, medicine, Neurology (clinical), Gene, medicine.drug

الوصف: As a rare subtype of glioblastomas (GBM), genetic features in cystic GBM (cGBM) are still largely unknown. We have previously identified a series of active T cell subsets and positive cytokines/chemocytokines in the cystic fluid of cGBMs, including IFN-gamma, IL-2, IL-6, IL-8, TNF-alpha, and MIP-1alpha/beta. This study aimed to evaluate the prognosis of cGBM through DNA methylation patterns and immune microenvironment transcriptional signatures. IvyGAP, EGA and fresh samples from a prospective Chinese cohort were collected to investigate genomic signatures, immune microenvironment and survival outcomes in patients with cGBMs. Gd T1-weighted, T2-weighted, T2-Flair, DWI or ADC images were used to classify cGBM. 143 cases with MGMT/IDH record were used to compare survival time and genomic analysis. Among the three cohorts, Kaplan-Meier analysis showed cystic features have benefit to overall survival (OS). Moreover, cyst feature is the forth factor (HR=0.65, [95% CI 0.42, 1.01]) of survival after IDH, MGMT and Stupp therapeutic regimen. Interestingly, in IDH-wild/MGMT-unmethyled subtype, cGBM patients have longer OS vs noncystic GBM (noncGBM) patients (HR = 0.57, [95% CI 0.33, 0.99]). Compared to noncGBM, cGBM patients have hypomethylation state both in whole gene region and cpG islands. Ivygap database showed between cystic and noncystic group, in sub-structures such as CT (cellular tumor region), CTpan (pseudopalisading cells around necrosis) and CTpnz (perinecrotic zone) there are differential gene expressions and different enrichment pathways. GSEA analysis showed within cGBM group, many gene sets associated with immune function activation such as TRL1/2/3/7 and IFN pathways. These results suggest that cysts of GBM may be associated with hypomethylation status an activated immune microenvironment which is associated with longer survival and may define a unique subgroup of GBM with intrinsically different biology and prognosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e5caa82d79ad25923f84af7ebb35a79cTest
https://europepmc.org/articles/PMC8598639Test/