tbuckley/cabot-search huggingface dataset:
Abstract 10958: Effect of Stage B HFpEF on Diastolic Peak Filling Rates in Obese Individuals, and the Impact of 1 Year of Exercise Training
Authors: Michinari Hieda, Christopher Hearon, Katrin Dias, Rakushumimarika Harada, Yogamaya Mantha, James MacNamara, Dean Palmer, Mitchel Samels, Braden Everding, Sheryl A Livingston, Margot Morris, Benjamin D Levine, Satyam Sarma
Journal: Circulation (2019)

Introduction: Obesity is an independent risk factor for the development of heart failure with preserved ejection fraction (HFpEF). Previously we demonstrated that HFpEF patients have an abnormal vo...
Differential chromatin accessibility landscape reveals structural and functional features of the allopolyploid wheat chromosomes
Authors: Katherine W. Jordan, Fei He, Monica Fernandez de Soto, Alina Akhunova, Eduard Akhunov
Journal: Genome biology (2020)

Abstract Background Our understanding of how the complexity of the wheat genome influences the distribution of chromatin states along the homoeologous chromosomes is limited. Using a differential nuclease sensitivity assay, we investigate the chromatin states of the coding and repetitive regions of the allopolyploid wheat genome. Results Although open chromatin is found to be significantly enriched around genes, the majority of MNase-sensitive regions are located within transposable elements (TEs). Chromatin of the smaller D genome is more accessible than that of the larger A and B genomes. Chromatin states of different TEs vary among families and are influenced by the TEs’ chromosomal position and proximity to genes. While the chromatin accessibility of genes is influenced by proximity to TEs, and not by their position on the chromosomes, we observe a negative chromatin accessibility gradient along the telomere-centromere axis in the intergenic regions, positively correlated with the distance between genes. Both gene expression levels and homoeologous gene expression bias are correlated with chromatin accessibility in promoter regions. The differential nuclease sensitivity assay accurately predicts previously detected centromere locations. SNPs located within more accessible chromatin explain a higher proportion of genetic variance for a number of agronomic traits than SNPs located within more closed chromatin. Conclusions Chromatin states in the wheat genome are shaped by the interplay of repetitive and gene-encoding regions that are predictive of the functional and structural organization of chromosomes, providing a powerful framework for detecting genomic features involved in gene regulation and prioritizing genomic variation to explain phenotypes.
Outcomes of Common Major Surgical Procedures in Older Adults With and Without Dementia
Authors: Rebecca Masutani, Ajinkya Pawar, Hemin Lee, Joel S. Weissman, Dae Hyun Kim
Journal: JAMA Network Open (2020)

This cross-sectional study uses data from the Premier Healthcare Database to compare in-hospital mortality, home discharge, and hospital length of stay among older adults with and without dementia who have undergone major surgical procedures.
Re: Vahdani et al.: Presentation and treatment of deep orbital dermoid cysts. (Ophthalmology. 2020 Mar 5;S0161-6420(20)30225-6. doi: 10.1016/j.ophtha.2020.02.037. Online ahead of print.)
Authors: Augustin Lecler, Mathieu Zmuda
Journal: Ophthalmology (2020)
Targeting EGFR-TK with radiolabeled cyclam-tyrosine
Authors: David J. Yang, Chang-Sok Oh, Mithu Chanda, Ali Azhdarinia, Richard Mendez, Dong-Fang Yu, Saady Kohanim, Jerry L. Bryant, Edmund Kim
Journal: Cancer Research (2006)

2394  Purpose. The epidermal growth factor receptor (EGFR) is expressed in a variety of human solid tumors. When EGFR is triggered, EGFR tyrosine kinase (TK) is activatedand leading to initiate the receptor-mediated signal transduction, cell proliferation, survival, angiogenesis, and metastasis. This study was to develop radiolabeled cyclam-tyrosine to assess EGFR-TK activity. Method. Cyclam-tyrosine was synthesized by conjugating O-3-tosylpropyltyrosine with cyclam N,N,N-tri (trifluoroacetate), followed by hydrolysis. In vitro cell culture were conducted using epidermoid carcinoma (A431), lung papillary adenocarcinoma (H441) and lung adenocarcinoma (H3255) cells. The cells (50,000 cells/well) were incubated with ZD1839 (gefitinib, 1-20 uM) for 1 hrs and Western blot was performed. Cellular uptake of 99mTc-cyclam-tyrosine (2 uCi/well) was conducted at 1.5 hrs after the cells (50,000 cells/well) were incubated with ZD1839 (gefitinib, 1-20 uM) for 6 hrs. The cellular upatek findings were correlated Western Blot assays Cyclam-tyrosine was also labeled with 68Ga (PET isotope). PET and planar imaging studies with 68Ga/ 99mTc-cyclam-tyrosine were conducted in tumor-bearing rodents. Results. Western blot analysis showed that high EGFR-TK expression (A431, H3255) could be inhibited with ZD1839 whereas poor EGFR-TK (H441) could not be inhibited. In vitro cellular uptake assays indicated that EGFR-TK activity correlated well with 99mTc-EC-DG. PET and planar scintigraphy in animal models demonstrated the tumor could be clearly visualized by 68Ga-cyclam-tyrosine and 99mTc-cyclam-tyrosine. Conclusion.. Radiolabeled cyclam-tyrosine could assess EGFR-TK activity in tumor cells. Such compounds may be useful in selecting patients who may respond to EGFR-TK therapy.
Semi-Quantitative Analysis of CD19 and CD22 Expression in B-Lymphoblastic Leukemia and Implications for Targerted Immunotherapy
Authors: Jaclyn Rosenthal, Ammar S. Naqvi, Gerald Wertheim, Michele Paessler, Susan R. Rheingold, Andrei Thomas-Tikhonenko, Vinodh Pillai
Journal: Blood (2017)
Cancer immunotherapy resistance based on immune checkpoints inhibitors: Targets, biomarkers, and remedies
Authors: Elisabeth Pérez-Ruiz, Ignacio Melero, Joanna Kopecka, Ana Bela Sarmento-Ribeiro, Marilina García-Aranda, Javier De Las Rivas
Journal: Drug Resistance Updates (2020)

Cancer is one of the main public health problems in the world. Systemic therapies such as chemotherapy and more recently target therapies as well as immunotherapy have improved the prognosis of this large group of complex malignant diseases. However, the frequent emergence of multidrug resistance (MDR) mechanisms is one of the major impediments towards curative treatment of cancer. While several mechanisms of drug chemoresistance are well defined, resistance to immunotherapy is still insufficiently unclear due to the complexity of the immune response and its dependence on the host. Expression and regulation of immune checkpoint molecules (such as PD-1, CD279; PD-L1, CD274; and CTLA-4, CD152) play a key role in the response to immunotherapy. In this regard, immunotherapy based on immune checkpoints inhibitors (ICIs) is a common clinical approach for treatment of patients with poor prognosis when other first-line therapies have failed. Unfortunately, about 70 % of patients are classified as non-responders, or they progress after initial response to these ICIs. Multiple factors can be related to immunotherapy resistance: characteristics of the tumor microenvironment (TME); presence of tumor infiltrating lymphocytes (TILs), such as CD8 + T cells associated with treatment-response; presence of tumor associated macrophages (TAMs); activation of certain regulators (like PIK3γ or PAX4) found present in non-responders; a low percentage of PD-L1 expressing cells; tumor mutational burden (TMB); gain or loss of antigen-presenting molecules; genetic and epigenetic alterations correlated with resistance. This review provides an update on the current state of immunotherapy resistance presenting targets, biomarkers and remedies to overcome such resistance.
Sequential Duo–Peptide Receptor Radionuclide Therapy With Indigenous 90Y-DOTATATE and 177Lu-DOTATATE in Large-Volume Neuroendocrine Tumors
Authors: Rahul V. Parghane, Arpit Mitra, Trupti Upadhye, Sutapa Rakshit, Sharmila Banerjee, Sandip Basu
Journal: Clinical Nuclear Medicine (2020)

Abstract The efficacy of 177 Lu-DOTATATE in large neuroendocrine tumors (NETs) is reduced because of the lower energy (Eβmax 0.497 MeV) and shorter range of 177 Lu. The pure β-emitter 90 Y with its longer β range is more effective in larger tumors. This should be balanced with the greater risk of 90 Y-DOTATATE–related nephrotoxicity. Sequential duo–peptide receptor radionuclide therapy may result in a better response with minimal adverse effects in large-volume heterogeneous NETs. A 56-year-old man with large rectal NET liver metastases, treated with 90 Y-DOTATATE and 177 Lu-DOTATATE and sequential duo–peptide receptor radionuclide therapy, presented with post- 90 Y-DOTATATE bremsstrahlung and PET/CT in comparison with 68 Ga-DOTATATE PET/CT and 177 Lu-DOTATATE scans.
Amplification and overexpresssion of IKBKE activates NF-kB pathway in breast cancers.
Authors: Laura Mulvey, Jesse Boehm, Ian Dunn, So Young Kim, Jun Yao, William Hahn, Kornelia Polyak
Journal: Cancer Research (2007)

5261  Since the successful use of kinase inhibitors in the clinical setting (e.g., Gleevec and Iressa), kinases have become an area of intense focus in the search for oncogene candidates. Based on our array CGH (Comparative Genomic Hybridization) and SAGE (Serial Analysis of Gene Expression) data on breast tumors, we selected 22 kinases that were both amplified and overexpressed in breast tumors as candidate oncogenic kinases. Quantitative PCR (QPCR) was performed to verify amplification and overexpression of these kinases in 30 breast tumors using genomic DNA and cDNAs, respectively. The result was further confirmed using additional samples from 13 breast tumors which had not been analyzed by array CGH. This lead us to find 9 kinases that were amplified to different degrees in breast tumors and had concomitant overexpression when compared to normal breast tissues. Among these putative oncogenes we focused on IKBKE, which encode IkB kinase epsilon (IKKe), a kinase involved in NF-kB and interferon activation. Array CGH analysis and QPCR demonstrated that IKBKE was gained or amplified in at 10 of 30 breast tumors, which is accompanied by overexpression in at least 8 tumors. It is also amplified/gained and overexpressed in three breast cancer cell lines (ZR75-1, UACC812, and MCF-7). QPCR also detected overexpression of IKKe in non-amplified tumors and cell lines, suggesting other mechanisms are involved in IKKe upregulation. We demonstrated that overexpression of IKKe lead to transformation of kidney embryonic cells, while downregulation of IKKe by RNAi inhibited growth of ZR75-1 and MCF-7 breast cancer cells. Thus, IKBKE represents a promising oncogene candidate that function through activation of NF-kB in breast cancers and a promising therapeutic target.
Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis
Authors: Merlijn H. Kaaij, Melissa N. van Tok, Iris C. Blijdorp, Carmen A. Ambarus, Michael Stock, Désiree Pots, Véronique L. Knaup, Marietta Armaka, Eleni Christodoulou-Vafeiadou, Tessa K. van Melsen, Huriatul Masdar, Harry J.P.P. Eskes, Nataliya G. Yeremenko, George Kollias, Georg Schett, Sander W. Tas, Leonie M. van Duivenvoorde, Dominique L.P. Baeten
Journal: The Journal of Experimental Medicine (2020)

TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). It remains incompletely understood how TNF can lead to different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral osteoproliferative inflammation in SpA. We observed a marked increase of transmembrane (tm) versus soluble (s) TNF in SpA versus RA together with a decrease in the enzymatic activity of ADAM17. In contrast with the destructive polysynovitis observed in classical TNF overexpression models, mice overexpressing tmTNF developed axial and peripheral joint disease with synovitis, enthesitis, and osteitis. Histological and radiological assessment evidenced marked endochondral new bone formation leading to joint ankylosis over time. SpA-like inflammation, but not osteoproliferation, was dependent on TNF-receptor I and mediated by stromal tmTNF overexpression. Collectively, these data indicate that TNF can drive distinct inflammatory pathologies. We propose that tmTNF is responsible for the key pathological features of SpA.
Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma among women in Connecticut
Authors: Min Shen, Tongzhang Zheng, Qing Lan, Yawei Zhang, Shelia H. Zahm, Sophia S. Wang, Theodore R. Holford, Brian Leaderer, Meredith Yeager, Robert Welch, Dehaee Kang, Peter Boyle, Bing Zhang, Kaiyong Zou, Yong Zhu, Stephen Chanock, Nathaniel Rothman
Journal: Cancer Research (2006)

4583  Background: Several hereditary syndromes characterized by defective DNA repair are associated with high risk of non-Hodgkin lymphoma (NHL). To explore whether common polymorphisms in DNA repair genes affect risk of NHL in the general population, we evaluated the association between single nucleotide polymorphisms (SNP) in DNA repair genes and risk of NHL in a population-based case-control study among women in Connecticut. Methods: A total of 518 NHL cases and 597 controls recruited into the study provided a biologic sample. Thirty-two SNPs in 18 genes involved in several DNA repair pathways were genotyped including ERCC5, ERCC2, ERCC1, RAD23B, XPC, WRN, BRCA1, BRCA2, LIG4, NBS1, XRCC2, XRCC3, XRCC4, RAG1, XRCC1, ADPRT, APEX1, and MGMT. Genotype data were analyzed by unconditional logistic regression adjusting for age and race. Results: SNPs in four genes that participate in DNA nucleotide excision repair (NER: ERCC5 and ERCC2) and double strand break repair (DSBR: WRN and BRCA1) were associated with altered risk of all NHL, and were also significant for diffuse large B-cell lymphoma (DLBCL), the major B cell subtype. In particular, ERCC5 Asp1104His was associated with NHL overall (OR: 1.46; 95% CI: 1.13-1.88; P=0.004), DLBCL (OR: 1.44; 95% CI: 0.99-2.09; P=0.058), and also T cell lymphoma. WRN Cys1367Arg was associated with NHL overall (OR, 0.71, 95% CI, 0.56-0.91, P=0.007) and DLBCL (OR, 0.66, 95% CI, 0.45-0.95, P=0.024), as well as follicular and marginal zone lymphomas. Conclusion: Genetic polymorphisms in DNA repair genes, particularly ERCC5 and WRN, may play a role in the pathogenesis of NHL, especially for DLBCL. ERCC5 plays a role in NER and other biological processes, including base excision repair (BER) and transcription-coupled repair of oxidative damage. WRN is critical in maintaining genomic stability and participates in multiple DNA repair pathways including DSBR, BER and mismatch repair. Further work is needed to extend these findings by carrying out haplotype analyses of these and related genes and to replicate the observations in other studies.
Characteristics of cells with engraftment capacity within CD34+ cell population upon G-CSF and Plerixafor mobilization
Authors: Margaux Mombled, Laura Rodriguez, Maryse Avalon, Pascale Duchez, Marija Vlaski-Lafarge, Christelle Debeissat, Baptiste Pérard, Katherine M. Sawai, Jean Max Pasquet, Fontanet Bijou, Florian Thévenot, Txomin Cabantous, Zoran Ivanovic, Philippe Brunet de la Grange
Journal: Leukemia (2020)
Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function
Authors: Frederike A. Hartl, Esmeralda Beck-Garcìa, Nadine M. Woessner, Lea J. Flachsmann, Rubí M.-H. Velasco Cárdenas, Simon M. Brandl, Sanaz Taromi, Gina J. Fiala, Anna Morath, Pankaj Mishra, O. Sascha Yousefi, Julia Zimmermann, Nico Hoefflin, Maja Köhn, Birgitta M. Wöhrl, Robert Zeiser, Kristian Schweimer, Stefan Günther, Wolfgang W. Schamel, Susana Minguet
Journal: Nature Immunology (2020)
Adjuvant Systemic Chemotherapy vs Active Surveillance Following Up-front Resection of Isolated Synchronous Colorectal Peritoneal Metastases
Authors: Koen P. Rovers, Checca Bakkers, Felice N. van Erning, Jacobus W. A. Burger, Simon W. Nienhuijs, Geert A. A. M. Simkens, Geert-Jan M. Creemers, Patrick H. J. Hemmer, Cornelis J. A. Punt, Valery E. P. P. Lemmens, Pieter J. Tanis, Ignace H. J. T. de Hingh
Journal: JAMA Oncology (2020)

To date, there are no data on the value of adjuvant systemic chemotherapy following up-front resection of isolated synchronous colorectal peritoneal metastases.To assess the association between adjuvant systemic chemotherapy and overall survival following up-front resection of isolated synchronous colorectal peritoneal metastases.In this population-based, observational cohort study using nationwide data from the Netherlands Cancer Registry (diagnoses between January 1, 2005, and December 31, 2017; follow-up until January 31, 2019), 393 patients with isolated synchronous colorectal peritoneal metastases who were alive 3 months after up-front complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were included. Patients allocated to the adjuvant systemic chemotherapy group were matched (1:1) with those allocated to the active surveillance group by propensity scores based on patient-, tumor-, and treatment-level covariates.Adjuvant systemic chemotherapy, defined as systemic chemotherapy without targeted therapy, starting within 3 months postoperatively.Overall survival was compared between matched groups using Cox proportional hazards regression analysis adjusted for residual imbalance. A landmark analysis was performed by excluding patients who died within 6 months postoperatively. A sensitivity analysis was performed to adjust for unmeasured confounding by major postoperative morbidity.Of 393 patients (mean [SD] age, 61 [10] years; 181 [46%] men), 172 patients (44%) were allocated to the adjuvant systemic chemotherapy group. After propensity score matching of 142 patients in the adjuvant systemic chemotherapy group with 142 patients in the active surveillance group, adjuvant systemic chemotherapy was associated with improved overall survival compared with active surveillance (median, 39.2 [interquartile range, 21.1-111.1] months vs 24.8 [interquartile range, 15.0-58.4] months; adjusted hazard ratio [aHR], 0.66; 95% CI, 0.49-0.88; P = .006), which remained consistent after excluding patients who died within 6 months postoperatively (aHR, 0.68; 95% CI, 0.50-0.93; P = .02) and after adjustment for major postoperative morbidity (aHR, 0.71; 95% CI, 0.53-0.95).Findings of this study suggest that in patients undergoing up-front resection of isolated synchronous colorectal peritoneal metastases, adjuvant systemic chemotherapy appeared to be associated with improved overall survival. Although randomized trials are needed to address the influence of potential residual confounding and allocation bias on this association, results of this study may be used for clinical decision-making in this patient group for whom no data are available.
Re: Lisa Moris, Marcus G. Cumberbatch, Thomas Van den Broeck, et al. Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review. Eur Urol 2020;77:614–27
Authors: Satoshi Funada, Takashi Yoshioka, Yan Luo
Journal: European Urology (2020)
5-FU, Irinotecan, Nab-Paclitaxel in Gastrointestinal Cancers—Response
Authors: Manish R. Sharma, Smita S. Joshi, Hedy L. Kindler
Journal: Clinical Cancer Research (2020)

We would like to thank Maeda and colleagues for their letter regarding our article. They suggest that the dose of irinotecan should be escalated above 180 mg/m2 in patients with the UGT1A1 *1/*1 and *1/*28 genotypes. To support their view, they cited two studies that explored the safety and tolerability of dose-escalated irinotecan in the FOLFIRI regimen. We are certainly aware of these studies, as one of us (M.R. Sharma) was a coinvestigator on a genotype-guided dosing study of irinotecan in FOLFIRI plus bevacizumab, also published in Clinical Cancer Research (1). In that study, the MTD of irinotecan was 310 mg/m2 in *1/*1 patients and 260 mg/m2 in *1/*28 patients. However, we contend that FOLFIRINOX (rather than FOLFIRI) is the most analogous regimen to FOLFIRABRAX, as both are regimens with a third cytotoxic chemotherapy drug (oxaliplatin or nab-paclitaxel) in addition to 5-fluorouracil/leucovorin and irinotecan. In our previous study of genotype-guided modified FOLFIRINOX, we used the same doses of irinotecan as in the current study, and the percentage of dose-limiting toxicities observed led us to conclude that dose escalation of irinotecan above 180 mg/m2 in the *1/*1 and *1/*28 patients would be very unlikely to be tolerable (2).Maeda and colleagues contend that the irinotecan dose should be escalated "to enhance the therapeutic efficacy in wild-type and heterozygous patients." However, it should be noted that escalated doses of irinotecan in the FOLFIRI regimen have never been demonstrated to result in superior efficacy compared with standard doses in a randomized study. It would not be fair to assume that escalated doses of irinotecan in FOLFIRABRAX would result in higher response rates than those reported in the current study.See the original Letter to the Editor, p. 3889M.R. Sharma is an employee/paid consultant for Ipsen, Bayer, AbbVie, Taiho, Eisai, and Exelixis. H. Kindler is an employee/paid consultant for Inventiva, Aldeyra Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Erytech, Five Prime Therapeutics, Ipsen, Kyowa, Merck, and Paredox. No potential conflicts of interest were disclosed by the other author.