tbuckley/cabot-search huggingface dataset:
Plasma cfDNA in Glioblastoma—Response
Authors: Stephen J. Bagley, Erica L. Carpenter
Journal: Clinical Cancer Research (2020)

We appreciate the interest in our study from Takayasu and colleagues. They raise important issues which were largely addressed in our article but deserve further discussion.Takayasu and colleagues question whether variants detected in plasma in our study reflect tumor somatic mutations. We explain in the Discussion that "in the absence of next-generation sequencing (NGS) results for matched buffy coats, we cannot rule out the possibility that some mutations detected in cell-free DNA (cfDNA) might be reflective of clonal hematopoiesis" (1). Takayasu and colleagues also suggest that we should have sequenced cfDNA from healthy controls to address whether variants detected in plasma in our glioblastoma (GBM) cohort represent "sequencing artifacts." The plasma NGS panel used in this study, performed in a Clinical Laboratory Improvement Amendments–certified laboratory, has already been validated in prior studies using hundreds of healthy controls (2, 3), the vast majority of whom did not have somatic mutations detected in plasma. These prior validation articles (2, 3) also address the "analysis parameters and limit of detection of the assay," which Takayasu and colleagues describe as "not provided." Nonetheless, we agree that further studies are needed to understand which mutations detected in the plasma of patients with GBM are tumor derived. We also agree that cerebrospinal fluid, although not routinely collected in patients with GBM, has higher circulating tumor DNA concentration and better concordance with tissue sequencing. This, too, is already stated in the Discussion.Takayasu and colleagues also comment that "the authors stated that the discordance in mutations detected between tissue and plasma is partially due to tumor heterogeneity." We would like to emphasize the careful language used in the article: "These results may be explained in part by tumor heterogeneity." This is a hypothesis generated by our data, rather than a definitive conclusion. Consistent with this cautious interpretation, we openly acknowledge the low variant allele frequency (VAF) in our samples, stating that "prior studies have demonstrated higher false-negative rates for plasma NGS when VAF is less than 1%" and citing the same reference used by Takayusu and colleagues to make this point (4).Finally, we wish to point out that plasma NGS was only one component of our study and was not highlighted as the primary or most significant finding. Our data, which require validation in larger, independent cohorts, suggest a potential role for plasma cfDNA (agnostic to whether the DNA is tumor derived) as a prognostic biomarker and surrogate of tumor burden in GBM.See the original Letter to the Editor, p. 2275S. Bagley reports receiving other commercial research support from Guardant Health. No potential conflicts of interest were disclosed.
Amelioration of an Inherited Metabolic Liver Disease through Creation of a De Novo Start Codon by Cytidine Base Editing
Authors: Lei Yang, Liren Wang, Yanan Huo, Xi Chen, Shuming Yin, Yaqiang Hu, Xiaohui Zhang, Rui Zheng, Hongquan Geng, Honghui Han, Xueyun Ma, Meizhen Liu, Haibo Li, Weishi Yu, Mingyao Liu, Jun Wang, Dali Li
Journal: Molecular Therapy (2020)

Base editing technology efficiently generates nucleotide conversions without inducing excessive double-strand breaks (DSBs), which makes it a promising approach for genetic disease therapy. In this study, we generated a novel hereditary tyrosinemia type 1 (HT1) mouse model, which contains a start codon mutation in the fumarylacetoacetate hydrolase (Fah) gene by using an adenine base editor (ABE7.10). To investigate the feasibility of base editing for recombinant adeno-associated virus (rAAV)-mediated gene therapy, an intein-split cytosine base editor (BE4max) was developed. BE4max efficiently induced C-to-T conversion and restored the start codon to ameliorate HT1 in mice, but an undesired bystander mutation abolished the effect of on-target editing. To solve this problem, an upstream sequence was targeted to generate a de novo in-frame start codon to initiate the translation of FAH. After treatment, almost all C-to-T conversions created a start codon and restored Fah expression, which efficiently ameliorated the disease without inducing off-target mutations. Our study demonstrated that base editing-mediated creation of de novo functional elements would be an applicable new strategy for genetic disease therapy.
Simultaneous detection of both hepatitis B virus DNA and hepatitis C virus RNA using a combined one-step polymerase chain reaction technique*1, *2
Authors: K HU
Journal: Hepatology (1995)

Hepatitis C virus (HCV) RNA polymerase chain reaction (PCR) is widely used for diagnosis of HCV infection and evaluation of therapy. The sensitive hepatitis B virus (HBV) DNA PCR is often reserved for detection of quantities of HBV DNA that are insufficient for hybridization. Application of both PCR techniques is limited by their labor-intensity, potential for contamination, and substantial time required for analysis. To study HCV and HBV infections, occurring alone or in combination, we developed a combined one-step PCR method to detect HCV RNA and HBV DNA in a single serum specimen using oligoprimers from the HCV 5′ untranslated region and the HBV preS/S region. Specificity of the HBV and HCV PCR products was confirmed on the basis of their molecular sizes in positive samples, Southern blot hybridization, and negative controls. The sensitivities of the combined PCR were assessed using samples containing a wide range of defined amounts of HBV DNA and HCV RNA and were comparable with those obtained with conventional HBV DNA or HCV RNA PCR methods. The sensitivity of the combined method was further validated by the 100% concordance between results of its HBV and HCV components and those of conventional PCR methods in patients with HBV and/or HCV infections. The combined one-step HBV/HCV PCR is a sensitive, specific, rapid, and cost-effective method, especially suited for epidemiological screening and clinical diagnosis of HBV and HCV infections occurring alone or in combination.
AG-028262, a novel selective VEGFR tyrosine kinase antagonist that potently inhibits KDR signaling and angiogenesis in vitro and in vivo
Authors: Helen Y. Zou, Qiuhua Li, Maren Grazzini, Roslyn Dillon, Karin Amundson, Auzon Acena, Grant Wickman, Alicia Shelley, Dave Rewolinski, Scott Jacobs, Jim Solowiej, Brion Murray, Michele McTigue, William Romines, Jihong Lou, David Gale, Steve Bender, Robert Kania, David R. Shalinsky, Dana D. Hu-Lowe
Journal: Cancer Research (2004)

2578  Vascular endothelial growth factor (VEGF) and its receptors play key roles in tumor angiogenesis, growth, and metastasis. AG-028262 is a next-generation small molecule inhibitor designed to block the ATP kinase domain of human VEGFR2 (KDR, Flk-1) while sparing other related non-VEGF receptors. In enzymatic assays, AG-028262 had pM affinity for KDR, but ≥ nM affinities for other kinases, such as FGFR1 and Lck. In cellular assays, AG-028262 inhibited KDR autophosphorylation in response to VEGF stimulation with an IC50 of 0.34 nM, but was 568 and 1338-fold less potent for inhibiting related RTKs such as PDGFR-β and FGFR1, respectively. In human umbilical vein endothelial cells (HUVEC), AG-028262 inhibited VEGF-mediated survival with an IC50 of 0.73 nM compared to an IC50 of 154 nM for inhibiting bFGF-mediated survival. AG-028262 induced apoptosis in HUVECs concomitant with inhibition of cellular signaling downstream of KDR. AG-028262 also lacked anti-proliferative activity in vitro against many tumor cell lines at concentrations up to 10 μM. In vivo, oral administration of AG-028262 led to marked antitumor efficacy in several human tumor xenograft models, including MV522 carcinoma, U87 glioblastoma, and H526 lung carcinoma, and in the syngeneic Lewis lung carcinoma model. Immunohistochemistry studies showed that the compound significantly reduced microvessel density in tumors. PK/PD studies in A375 human melanoma xenografts and in the rat retina demonstrated potent and selective inhibition of KDR in vivo. In summary, AG-028262 is a potent and selective VEGF receptor tyrosine kinase inhibitor with marked antiangiogenic properties that may have utility in cancer therapy.
CONTEMPORARY NATIONAL TRENDS AND OUTCOMES OF INFERIOR VENA CAVA FILTER PLACEMENT IN CANCER PATIENTS WITH PROXIMAL LOWER EXTREMITY DEEP VEIN THROMBOSIS
Authors: Yevgeniy Brailovsky, Chad Zack, Harish Jarrett, Huaqing Zhao, Eric Choi, Wheatley Grayson, Riyaz Bashir
Journal: Journal of the American College of Cardiology (2014)
Abstract 16818: Diagnostic Yield of Emergent Coronary CT Angiography in Intermediate Risk Patients for Suspected Acute Coronary Syndrome: Results From an Emergency Department Registry
Authors: Jan-Erik Scholtz, Daniel Addison, Pedro Staziaki, Nina Meyersohn, Michael T Lu, Tomas G Neilan, Udo Hoffmann, Brian B Ghoshhajra
Journal: Circulation (2017)

Introduction: The utility of coronary CT angiography (CTA) has been rigorously established in emergency department (ED) patients at low-to-intermediate risk for acute coronary syndrome (ACS), with ...
Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents
Authors: Jyoti Roy, Suraj U Hettiarachchi, Miranda Kaake, Ramesh Mukkamala, Philip S Low
Journal: Theranostics (2020)

Background: Cancer-associated fibroblasts (CAFs) comprise a major cell type in the tumor microenvironment where they support tumor growth and survival by producing extracellular matrix, secreting immunosuppressive cytokines, releasing growth factors, and facilitating metastases. Because tumors with elevated CAFs are characterized by poorer prognosis, considerable effort is focused on developing methods to quantitate, suppress and/or eliminate CAFs. We exploit the elevated expression of fibroblast activation protein (FAP) on CAFs to target imaging and therapeutic agents selectively to these fibroblasts in solid tumors. Methods: FAP-targeted optical imaging, radioimaging, and chemotherapeutic agents were synthesized by conjugating FAP ligand (FL) to either a fluorescent dye, technetium-99m, or tubulysin B hydrazide. In vitro and in vivo studies were performed to determine the specificity and selectivity of each conjugate for FAP in vitro and in vivo. Results: FAP-targeted imaging and therapeutic conjugates showed high binding specificity and affinity in the low nanomolar range. Injection of FAP-targeted 99mTc into tumor-bearing mice enabled facile detection of tumor xenografts with little off-target uptake. Optical imaging of malignant lesions was also readily achieved following intravenous injection of FAP-targeted near-infrared fluorescent dye. Finally, systemic administration of a tubulysin B conjugate of FL promoted complete eradication of solid tumors with no evidence of gross toxicity to the animals. Conclusion: In view of the near absence of FAP on healthy cells, we conclude that targeting of FAP on cancer-associated fibroblasts can enable highly specific imaging and therapy of solid tumors.
Novel peptide linkers for highly potent antibody-auristatin conjugates
Authors: Svetlana Doronina, Tim Bovee, Damon Meyer, Peter Senter
Journal: Cancer Research (2008)

4907   A great deal of interest has surrounded the use of monoclonal antibodies (mAbs) for the selective delivery of cytotoxic agents to tumor cells. We have previously demonstrated that mAb-auristatin conjugates are highly active, leading to cures and regressions of established tumors in nude mice. These antibody-drug conjugates (ADCs) contain a dipeptide valine-citrulline-p-aminobenzylcarbamate (vc-PABC) linker used to join the antimitotic drugs monomethylauristatin E or F (MMAE, MMAF) to a series of antitumor mAbs. This linker was selected for plasma stability and cleavage by lysosomal enzymes such as cathepsin B. Here, we describe several other dipeptide sequences, many of which are not cathepsin B substrates, for the attachment of auristatins to mAb carriers. More than 20 mAb-dipeptide-PABC-MMAF ADCs were prepared, all of which were active in vitro and in vivo independent of peptide sequence. There was no apparent improvement over the vc-PABC linker, since the PABC group facilitated lysosomal drug release. In contrast, a new series of mAb-MMAF conjugates was prepared in which the dipeptide linkers were directly attached to the C-terminal phenylalanine on the drug without using an intervening PABC spacer. Many of the dipeptide sequences contained unnatural amino acids in order to increase the stringency of drug release. Peptide sequences were identified within the new conjugates that led to both greater tolerability and higher potency compared to corresponding vc-PABC ADCs. The new linkers play an important role in ADC activity and tolerability, and mAb-auristatin conjugates derived from them are candidates for future development.
Efficacy of Twice Daily Fluticasone Propionate and Formoterol Fumarate Combination Administered Using an HFA pMDI in Patients with Mild to Moderate Asthma
Authors: A.D. D'Urzo, R.A. Nathan, K. Kaiser, C.L. Renz, R.I. Jain, R.J. Perdok, T.T. Doan
Journal: Journal of Allergy and Clinical Immunology (2009)
The role of systemic therapies in the development of lung sequelae after conformal radiotherapy in breast cancer patients.
Authors: Z Varga, A Cserháti, K Boda, L Thurzó, Z Kahán
Journal: Cancer Research (2009)

Abstract Abstract #4125 Some data suggest that adjuvant systemic therapies like tamoxifen and paclitaxel play a role in the development of radiogenic lung toxicity.&amp;#x2028; Early and late radiogenic lung sequelae were prospectively studied in patients receiving sequential taxane-based chemotherapy (Tax), concomittant hormone therapy with tamoxifen (Tam) or aromatase inhibitor (AI), or no systemic therapy (C) according to the institutional guidelines. Clinical signs, radiologic abnormalities and the mean lung density changes measured at the level of the left heart ventricle (MDCLHV) and the head of the clavicle (MDCHC) of the irradiated lung on CT were evaluated according to Kahan et al., Int. J. Radiat. Oncol. Biol. Phys., 2007.&amp;#x2028; The incidence of pneumonitis grade I with or without clinical symptoms did not significantly differ between the 4 groups. None of the patients developed symptomatic radiogenic lung fibrosis one year after the radiotherapy, however, radiogenic CT changes were significantly more frequent in the group treated with Tam. No differences in the MDCLHV and MDCHC values according to systemic therapy were detected 3 months or 1 year after the radiotherapy (Table). Significant positive associations existed between radiogenic lung changes with or without clinical symptoms and the age of the patient, the ipsilateral mean lung dose (MLD), the volume of the ipsilateral lung receiving ≥20 Gy (V20 Gy) and the irradiation of the axillary and supraclavicular lymph nodes. Extended data and statistical analysis including multiple linear regression and multivariate logistic regression models will be presented.&amp;#x2028; &amp;#x2028; &amp;#x2028; &amp;#x2028; Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4125.
Which treatment is most effective for patients with Achilles tendinopathy? A living systematic review with network meta-analysis of 29 randomised controlled trials
Authors: Arco C van der Vlist, Marinus Winters, Adam Weir, Clare L Ardern, Nicky J Welton, Deborah M Caldwell, Jan A N Verhaar, Robert-Jan de Vos
Journal: British Journal of Sports Medicine (2020)

Objective To provide a consistently updated overview of the comparative effectiveness of treatments for Achilles tendinopathy. Design Living systematic review and network meta-analysis. Data sources Multiple databases including grey literature sources were searched up to February 2019. Study eligibility criteria Randomised controlled trials examining the effectiveness of any treatment in patients with both insertional and/or midportion Achilles tendinopathy. We excluded trials with 10 or fewer participants per treatment arm or trials investigating tendon ruptures. Data extraction and synthesis Reviewers independently extracted data and assessed the risk of bias. We used the Grading of Recommendations Assessment, Development and Evaluation to appraise the certainty of evidence. Primary outcome measure The validated patient-reported Victorian Institute of Sport Assessment-Achilles questionnaire. Results 29 trials investigating 42 different treatments were included. 22 trials (76%) were at high risk of bias and 7 (24%) had some concerns. Most trials included patients with midportion tendinopathy (86%). Any treatment class seemed superior to wait-and-see for midportion Achilles tendinopathy at 3 months (very low to low certainty of evidence). At 12 months, exercise therapy, exercise+injection therapy and exercise+night splint therapy were all comparable with injection therapy for midportion tendinopathy (very low to low certainty). No network meta-analysis could be performed for insertional Achilles tendinopathy. Summary/conclusion In our living network meta-analysis no trials were at low risk of bias and there was large uncertainty in the comparative estimates. For midportion Achilles tendinopathy, wait-and-see is not recommended as all active treatments seemed superior at 3-month follow-up. There seems to be no clinically relevant difference in effectiveness between different active treatments at either 3-month or 12-month follow-up. As exercise therapy is easy to prescribe, can be of low cost and has few harms, clinicians could consider starting treatment with a calf-muscle exercise programme. PROSPERO registration number CRD42018086467.
Efficient gene knockout in primary human and murine myeloid cells by non-viral delivery of CRISPR-Cas9
Authors: Emily C. Freund, Jaclyn Y. Lock, Jaehak Oh, Timurs Maculins, Lelia Delamarre, Christopher J. Bohlen, Benjamin Haley, Aditya Murthy
Journal: The Journal of Experimental Medicine (2020)

Myeloid cells play critical and diverse roles in mammalian physiology, including tissue development and repair, innate defense against pathogens, and generation of adaptive immunity. As cells that show prolonged recruitment to sites of injury or pathology, myeloid cells represent therapeutic targets for a broad range of diseases. However, few approaches have been developed for gene editing of these cell types, likely owing to their sensitivity to foreign genetic material or virus-based manipulation. Here we describe optimized strategies for gene disruption in primary myeloid cells of human and murine origin. Using nucleofection-based delivery of Cas9-ribonuclear proteins (RNPs), we achieved near population-level genetic knockout of single and multiple targets in a range of cell types without selection or enrichment. Importantly, we show that cellular fitness and response to immunological stimuli is not significantly impacted by the gene editing process. This provides a significant advance in the study of myeloid cell biology, thus enabling pathway discovery and drug target validation across species in the field of innate immunity.
Abstract 15219: Dynamic Solid State SPECT Evaluation of Myocardial Blood Flow in Hemodialysis Patients
Authors: Ricardo A Nieves, Joseph Dietz, Prem Soman
Journal: Circulation (2019)

Introduction: Dialysis confers an elevated cardiac risk that may be mediated by abnormalities in myocardial blood flow. Recent advances in SPECT technology have enabled myocardial blood flow quanti...
Delta-like ligand 4 (Dll4) is critical for tumor growth and angiogenesis.
Authors: Irene Noguera, Sandra Coetzee, Patricia Boland, Nicholas Gale, George Yancopoulos, Gavin Thurston
Journal: Cancer Research (2006)

5705  The Delta-like/Notch signaling pathway is necessary to establish an organized and hierarchical vasculature during development. Targeted deletions of various Delta-like/Notch genes result in mice that die during development due to severe vascular defects. Using microarray analysis, we previously identified Delta-like ligand 4 (Dll4) as a VEGF-regulated gene in mouse xenograft tumor models. In addition, we found that in these tumor models, Dll4 expression was significantly higher in tumor vessels compared to those in adjacent normal skin. To explore the effects of blocking Dll4/Notch signaling in tumors, we performed xenograft studies in mice, where a soluble Dll4-Fc molecule was delivered locally by retrovirally mediated overexpression in tumor cells or was delivered systemically using an adenoviral approach. We found that both methods of delivering Dll4-Fc resulted in reduced tumor growth compared to controls. Additionally, Dll4-Fc treated tumor vessels were more highly branched than controls, forming fine networks with dense vascular sprouting. As revealed by expression analysis, these effects were apparently associated with a decrease in Notch signaling. These findings show that Dll4 plays a key role in tumor angiogenesis, and suggest that Dll4 may be an attractive potential target for the development of anti-angiogenic therapies.
Annals Graphic Medicine - Attending on the Medicine Wards
Authors: Zachary G. Jacobs
Journal: Annals of Internal Medicine (2020)

Web Exclusives19 May 2020Annals Graphic Medicine - Attending on the Medicine WardsFREEZachary G. Jacobs, MDZachary G. Jacobs, MDOregon Health & Science University, Portland, Oregon (Z.G.J.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G19-0036 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Oregon Health & Science University, Portland, Oregon (Z.G.J.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G19-0036.Author/Illustrator Information: Zachary G. Jacobs, MD, is a hospitalist at Oregon Health & Science University. He uses creative writing, photography, and graphic arts to combine his two passions: healing and storytelling. To see more of his work, visit https://zgjmd.wordpress.com. E-mail: [email protected]edu; Twitter: @ZacharyGJacobs.This article was published at Annals.org on 12 May 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 May 2020Volume 172, Issue 10Page: W132-W133KeywordsConflicts of interestDisclosureHealth careHealth information technologyHospitalistsPhotography ePublished: 12 May 2020 Issue Published: 19 May 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...