tbuckley/cabot-search huggingface dataset:
Abstract PO-056: Sonographic and photoacoustic monitoring of radiation-induced parenchymal and vascular injury to salivary glands
Authors: Eftekhar Rajab Bolookat, Vui King Vincent-Chong, Anurag K. Singh, Mukund Seshadri
Journal: Clinical Cancer Research (2021)

Abstract Salivary gland dysfunction is a common side effect of radiation therapy (RT) in patients with head and neck cancer and is a consequence of direct damage to glandular parenchyma along with inflammatory changes and vascular injury following radiation. However, dynamic functional imaging of changes in salivary gland vascularity and oxygenation following RT has not been previously reported. Here, we employed bimodal photoacoustic imaging (PAI) with co-registered ultrasound (US) to non-invasively monitor radiation-induced parenchymal and vascular injury to salivary glands in vivo. Experimental imaging studies revealed parenchymal damage on B-mode US and early increase in vascular resistance on contrast-enhanced US (within 24h following radiation). Notably, this was accompanied by a reduction in oxygen consumption of salivary glands on dynamic PAI following parasympathetic stimulation with pilocarpine. Temporal kinetics of radiation-induced vascular injury was dependent on the host immune status and correlates with stimulated salivary secretion. These findings demonstrate the ability of US-PAI to monitor the dynamic changes in neurovascular coupling of salivary glands following radiation injury and highlight its potential utility to identify drugs or therapeutic approaches that could protect or mitigate radiation-induced vascular damage. Citation Format: Eftekhar Rajab Bolookat, Vui King Vincent-Chong, Anurag K. Singh, Mukund Seshadri. Sonographic and photoacoustic monitoring of radiation-induced parenchymal and vascular injury to salivary glands [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-056.
A case series on the use of steroids and mycophenolate mofetil in idiopathic and heritable pulmonary veno-occlusive disease: is there a role for immunosuppression?
Authors: Carmel Bergbaum, Chinthaka B. Samaranayake, Alex Pitcher, Emma Weingart, Thomas Semple, Maria Kokosi, Athol U. Wells, David Montani, Konstantinos Dimopoulos, Colm McCabe, Aleksander Kempny, Carl Harries, Elizabeth Orchard, S. John Wort, Laura C. Price
Journal: European Respiratory Journal (2021)

<b>Patients with heritable and idiopathic PVOD have few therapeutic options. On suspicion of immune dysregulation, methylprednisolone or oral prednisolone then mycophenolate mofetil was trialled in three cases, with resulting clinical improvement/stability.</b>https://bit.ly/376mwR9
How Accurately does PSMA Inhibitor 18F-DCFPyL-PET-CT Image Prostate Cancer?
Authors: Lawrence D. True, Delphine L. Chen
Journal: Clinical Cancer Research (2021)

Abstract Current techniques for imaging prostate cancer (CT, MRI, and PET agents 18F-fluorodeoxyglucose, 11C-choline, 11C-acetate, and 18F-fluciclovine) are limited in sensitivity and specificity. PSMA PET agent 68Ga-PSMA-11 has recently been approved by the FDA. We comment on the performance of novel PSMA agent 18F-DCFPyL-PET/CT. See related article by Morris et al., p. 3674
Abstract IA-021: Predicting radiotherapy outcomes: Radiogenomics and risk of radiotherapy toxicity
Authors: Catharine M.L. West
Journal: Clinical Cancer Research (2021)

Abstract A key challenge in radiotherapy is to maximize radiation doses to cancer while minimizing damage to surrounding healthy tissues. As toxicity in a minority of patients limits the doses that can be safely given to the majority, there is interest in developing a test to measure an individual’s radiosensitivity before treatment and predict their likelihood of developing toxicity. A biomarker that predicts a cancer patient’s risk of toxicity could be used to personalize dose prescriptions or to offer alternative treatments. Many approaches have been studied to measure radiosensitivity. The development of omics technologies underpinned genome wide association studies (GWAS) attempting to identify genetic variants reported as single nucleotide polymorphisms (SNPs). The advantages of the approach include: a genetic test will be easier to implement clinically than a functional assay; a genetic test will not suffer from the poor reproducibility associated with some radiosensitivity testing methods; and SNPs are the most common type of genetic variation and so easiest to identify. Omics technologies offer promise, but to have an impact on radiotherapy practice research must identify biomarkers that replicate across cohorts. Robust replication needs big data, which is only possible with large collaborative efforts. The need for big data was addressed by establishing an international Radiogenomics Consortium. The latest results from the consortium will be presented including the largest radiogenomics study carried out to date involved ~4,000 men with prostate cancer. Citation Format: Catharine M.L. West. Predicting radiotherapy outcomes: Radiogenomics and risk of radiotherapy toxicity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-021.
Engineering protein theranostics using bio-orthogonal asparaginyl peptide ligases
Authors: Zhen Wang, Dingpeng Zhang, Xinya Hemu, Side Hu, Janet To, Xiaohong Zhang, Julien Lescar, James P. Tam, Chuan-Fa Liu
Journal: Theranostics (2021)

Background: Protein theranostics integrate both diagnostic and treatment functions on a single diseasetargeting protein.However, the preparation of these multimodal agents remains a major challenge.Ideally, conventional recombinant proteins should be used as starting materials for modification with the desired detection and therapeutic functionalities, but simple chemical strategies that allow the introduction of two different modifications into a protein in a site-specific manner are not currently available.We recently discovered two highly efficient peptide ligases, namely butelase-1 and VyPAL2.Although both ligate at asparaginyl peptide bonds, these two enzymes are bio-orthogonal with distinguishable substrate specificities, which can be exploited to introduce distinct modifications onto a protein. Methods:We quantified substrate specificity differences between butelase-1 and VyPAL2, which provide orthogonality for a tandem ligation method for protein dual modifications.Recombinant proteins or synthetic peptides engineered with the preferred recognition motifs of butelase-1 and VyPAL2 at their respective C-and N-terminal ends could be modified consecutively by the action of the two ligases.Results: Using this method, we modified an EGFR-targeting affibody with a fluorescein tag and a mitochondrion-lytic peptide at its respective N-and C-terminal ends.The dual-labeled protein was found to be a selective bioimaging and cytotoxic agent for EGFR-positive A431 cancer cells.In addition, the method was used to prepare a cyclic form of the affibody conjugated with doxorubicin.Both modified affibodies showed increased cytotoxicity to A431 cells by 10-and 100-fold compared to unconjugated doxorubicin and the free peptide, respectively.Conclusion: Bio-orthogonal tandem ligation using two asparaginyl peptide ligases with differential substrate specificities is a straightforward approach for the preparation of multifunctional protein biologics as potential theranostics.
Arrhythmogenesis in the aged heart following ischaemia–reperfusion: role of transient receptor potential vanilloid 4
Authors: Deborah Peana, Luis Polo-Parada, Timothy L Domeier
Journal: Cardiovascular Research (2021)

Abstract Aims Cardiomyocyte Ca2+ homoeostasis is altered with ageing and predisposes the heart to Ca2+ intolerance and arrhythmia. Transient receptor potential vanilloid 4 (TRPV4) is an osmotically activated cation channel with expression in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in Ca2+ handling and arrhythmogenesis following ischaemia–reperfusion (I/R), a pathological scenario associated with osmotic stress. Methods and results Cardiomyocyte membrane potential was monitored prior to and following I/R in Langendorff-perfused hearts of Aged (19–28 months) male and female C57BL/6 mice ± TRPV4 inhibition (1 μM HC067047, HC). Diastolic resting membrane potential was similar between Aged and Aged HC at baseline, but following I/R Aged exhibited depolarized diastolic membrane potential vs. Aged HC. The effects of TRPV4 on cardiomyocyte Ca2+ signalling following I/R were examined in isolated hearts of Aged cardiac-specific GCaMP6f mice (±HC) using high-speed confocal fluorescence microscopy, with cardiomyocytes of Aged exhibiting an increased incidence of pro-arrhythmic Ca2+ signalling vs. Aged HC. In the isolated cell environment, cardiomyocytes of Aged responded to sustained hypoosmotic stress (250mOsm) with an increase in Ca2+ transient amplitude (fluo-4) and higher incidence of pro-arrhythmic diastolic Ca2+ signals vs. Aged HC. Intracardiac electrocardiogram measurements in isolated hearts following I/R revealed an increased arrhythmia incidence, an accelerated time to ventricular arrhythmia, and increased arrhythmia score in Aged vs. Aged HC. Aged exhibited depolarized resting membrane potential, increased pro-arrhythmic diastolic Ca2+ signalling, and greater incidence of arrhythmia when compared with Young (3–5 months). Conclusion TRPV4 contributes to pro-arrhythmic cardiomyocyte Ca2+ signalling, electrophysiological abnormalities, and ventricular arrhythmia in the aged mouse heart.
Screening for Vitamin D Deficiency in Adults
Authors: Alex H. Krist, Karina W. Davidson, Carol M. Mangione, Michael Cabana, Aaron B. Caughey, Esa M. Davis, Katrina E. Donahue, Chyke A. Doubeni, John W. Epling, Martha Kubik, Li Li, Gbenga Ogedegbe, Douglas K. Owens, Lori Pbert, Michael Silverstein, James Stevermer, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2021)

<h3>Importance</h3> Vitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency. <h3>Objective</h3> To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment. <h3>Population</h3> Community-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended. <h3>Evidence Assessment</h3> The USPSTF concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined. <h3>Recommendation</h3> The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults. (I statement)
Pulmonary myeloid cell uptake of biodegradable nanoparticles conjugated with an anti-fibrotic agent provides a novel strategy for treating chronic allergic airways disease
Authors: Amlan Chakraborty, Anita A. Pinar, Maggie Lam, Jane E. Bourke, Simon G. Royce, Cordelia Selomulya, Chrishan S. Samuel
Journal: Biomaterials (2021)
Single-cell multi-omics analysis of the immune response in COVID-19
Authors: Emily Stephenson, Gary Reynolds, Rachel A. Botting, Fernando J. Calero-Nieto, Michael D. Morgan, Zewen Kelvin Tuong, Karsten Bach, Waradon Sungnak, Kaylee B. Worlock, Masahiro Yoshida, Natsuhiko Kumasaka, Katarzyna Kania, Justin Engelbert, Bayanne Olabi, Jarmila Stremenova Spegarova, Nicola K. Wilson, Nicole Mende, Laura Jardine, Louis C. S. Gardner, Issac Goh, Dave Horsfall, Jim McGrath, Simone Webb, Michael W. Mather, Rik G. H. Lindeboom, Emma Dann, Ni Huang, Krzysztof Polanski, Elena Prigmore, Florian Gothe, Jonathan Scott, Rebecca P. Payne, Kenneth F. Baker, Aidan T. Hanrath, Ina C. D. Schim van der Loeff, Andrew S. Barr, Amada Sanchez-Gonzalez, Laura Bergamaschi, Federica Mescia, Josephine L. Barnes, Eliz Kilich, Angus de Wilton, Anita Saigal, Aarash Saleh, Sam M. Janes, Claire M. Smith, Nusayhah Gopee, Caroline Wilson, Paul Coupland, Jonathan M. Coxhead, Vladimir Yu Kiselev, Stijn van Dongen, Jaume Bacardit, Hamish W. King, Anthony J. Rostron, A. John Simpson, Sophie Hambleton, Elisa Laurenti, Paul A. Lyons, Kerstin B. Meyer, Marko Z. Nikolić, Christopher J. A. Duncan, Kenneth G. C. Smith, Sarah A. Teichmann, Menna R. Clatworthy, John C. Marioni, Berthold Göttgens, Muzlifah Haniffa
Journal: Nature Medicine (2021)

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16
Chronic pain (primary and secondary) in over 16s: summary of NICE guidance
Authors: Serena Carville, Margaret Constanti, Nick Kosky, Cathy Stannard, Colin Wilkinson
Journal: BMJ (2021)

### What you need to know

Chronic pain—defined as pain that lasts for more than three months—is common, debilitating, and often difficult to treat.1 Chronic pain is classified in ICD-11 as being either primary or secondary. In chronic primary pain there is no clear underlying condition that adequately accounts for the pain or its impact; chronic secondary pain is pain linked to an underlying condition.2 Clinical judgment is required to determine whether the pain is primary, secondary, or a combination of the two (box 1).

Box 1 
### Identifying chronic primary pain

Chronic primary pain has no clear underlying condition, or the pain or its impact seems to be out of proportion to any observable injury or disease. All forms of pain can cause distress and disability, but these features are particularly prominent in presentations of chronic primary pain.

The guideline is consistent with the ICD-11 definition of chronic primary pain: “Chronic primary pain is chronic pain in one or more anatomical regions that is characterised by significant emotional distress (anxiety, anger/frustration or depressed mood) or functional disability (interference in daily life activities and reduced participation in social roles). Chronic primary pain is multifactorial: biological, psychological and social factors contribute to the pain syndrome. The diagnosis is appropriate independently of identified biological or psychological contributors unless another diagnosis would better account for the presenting symptoms.”4RETURN TO TEXT

This article summarises recommendations from the National Institute for Health and Care Excellence (NICE) guideline for chronic pain (primary and secondary) in people over 16 years old for use in all NHS settings where pain is managed.3 The …
Human breast microbiome correlates with prognostic features and immunological signatures in breast cancer
Authors: Alice Tzeng, Naseer Sangwan, Margaret Jia, Chin-Chih Liu, Karen S. Keslar, Erinn Downs-Kelly, Robert L. Fairchild, Zahraa Al-Hilli, Stephen R. Grobmyer, Charis Eng
Journal: Genome Medicine (2021)

Currently, over half of breast cancer cases are unrelated to known risk factors, highlighting the importance of discovering other cancer-promoting factors. Since crosstalk between gut microbes and host immunity contributes to many diseases, we hypothesized that similar interactions could occur between the recently described breast microbiome and local immune responses to influence breast cancer pathogenesis.
Abstract 12151: Exposure to Ambient Air Pollution and Coronary Calcification
Authors: Quan Huynh, Prasanna Venkataraman, Luke Knibbs, Fay Johnston, Thomas H Marwick
Journal: Circulation (2019)

Background: The association of air pollution with cardiovascular morbidity and mortality has been attributed to acute events (atherothrombosis). It is unclear whether air pollution may influence th...
Exosomal transfer of osteoclast-derived miRNAs to chondrocytes contributes to osteoarthritis progression
Authors: Jin Liu, Xiaohao Wu, Jun Lu, Guangxin Huang, Lei Dang, Huarui Zhang, Chuanxin Zhong, Zongkang Zhang, Dijie Li, Fangfei Li, Chao Liang, Yuanyuan Yu, Bao-Ting Zhang, Lin Chen, Aiping Lu, Ge Zhang
Journal: Nature Aging (2021)
Abstract IA-016: Metabolic deregulation drives a redox vulnerability in pancreatic cancer
Authors: Marianne Koritzinsky, Pallavi Jain, Anna Dvorkin-Gheva, Lucie Malbeteau, Piriththiv Dhavarasa, Kevin R. Brown, Gun Ho Jang, Parth Vora, Faiyaz Notta, Jason Moffat, Paul C. Boutros
Journal: Clinical Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an almost universally fatal malignancy and there is an urgent need for new therapeutic targets. PDAC cells harbor genetic alterations and display metabolic changes that render them vulnerable to perturbations in redox homeostasis. Peroxiredoxin 4 (PRDX4) supports redox homeostasis by metabolizing H2O2 in the endoplasmic reticulum (ER). Based on functional genomics, we found that PDAC cell lines are dependent on PRDX4 for their growth and survival. We validated this dependency in established and primary PDAC cells, as well as in 3D models and orthotopic xenografts. PRDX4 depletion led to increased levels of reactive oxygen species (ROS). Tumor cells are exposed to fluctuating oxygen levels, which are known to augment ROS production. In line with this, PRDX4 addiction was also exacerbated in cells exposed to hypoxia and reoxygenation. Cell death induced by PRDX4 depletion was accompanied by DNA damage and a DNA-PKcs-governed DNA damage response. As such, PRDX4 depletion also sensitized cells and tumors to ionizing radiation. The source of ROS that created a dependency on PRDX4 was attributed to NADPH oxidase 4 (NOX4), which localizes to the ER membrane. The functional requirement for PRDX4 was correlated with cellular NADPH levels across different models of PDAC and could be rescued by depletion of NOX4 or NADPH. As such, this study has identified NOX4 as a link between metabolic deregulation and ER-specific redox vulnerability in PDAC. Since PRDX4 is not an essential gene in normal tissues, our work also suggests that PRDX4 represents a novel therapeutic target for pancreatic cancer that may be particularly potent in combination with radiotherapy. Citation Format: Marianne Koritzinsky, Pallavi Jain, Anna Dvorkin-Gheva, Lucie Malbeteau, Piriththiv Dhavarasa, Kevin R. Brown, Gun Ho Jang, Parth Vora, Faiyaz Notta, Jason Moffat, Paul C. Boutros. Metabolic deregulation drives a redox vulnerability in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-016.
Abstract 11233: Healthcare and Health Disparities and Their Impact on Resource Utilization and Cost After Transcatheter Aortic Valve Replacement: A Nationwide Analysis of Real-world Data
Authors: Setri Fugar, Alexis K Okoh, Swaiman Singh, Aakash Garg, Devangi Dave, Chunguang Chen, Bruce N Haik, Marc Cohen, Leonard Lee, Mark Russo
Journal: Circulation (2019)

Objective: We sought to investigate health and healthcare disparities in the treatment of aortic stenosis with transcatheter aortic valve replacement (TAVR) and how they affect outcomes and resourc...
Abstract 12266: Long-Term Treatment with the SIRT1 Activator Resveratrol Ameliorates Cardiomyopathy in Dystrophin-Deficient Mice
Authors: Atsushi Kuno, Yusuke Hori, Masaya Tanno, Hidemichi Kouzu, Takahito Itoh, Daisuke Sunaga, Yoshiyuki Horio, Tetsuji Miura
Journal: Circulation (2011)

Background: Loss of cardiac dystrophin eventually leads to cardiac dysfunction and heart failure, which is a main cause of death in patients with Duchenne muscular dystrophy (DMD). However, there i...
Inhibition of tumor growth by DNA vaccines encoding TRAIL receptor DR5
Authors: Jessica Back, Gen Wu, Marie Piechocki, Richard Jones, Hideo Yagita, Wei-Zen Wei
Journal: Cancer Research (2008)

2872  Engagement of TRAIL with cognate death receptors (DR) induces apoptotic tumor cell death in preclinical models but TRAIL resistant cancers are often encountered. Results from Phase I clinical trials with mAb to human DR4/5 showed limited toxicity and stable disease in some cases. We hypothesize that induction of anti-DR Ab by active vaccination will provide protective anti-tumor immunity. To test this hypothesis, BALB/c mice were depleted of regulatory T cells and immunized 3-4 times by intramuscular electro-vaccination with plasmid DNA encoding the extracellular and transmembrane domains of mouse DR5 (mDR5) fused at the C-terminus with domain 1 of tetanus toxin fragment C (pmDR5ectm-Td.1). The level of vaccine-induced anti-mDR5 Ab was measured by flow cytometry via specific binding to D2F2 mouse mammary tumor cells transiently transfected with pmDR5ectm/GFP containing mDR5ectm sequence regulated by pCMV promoter followed by eGFP under an IRES sequence; therefore, transfected cells expressing the recombinant mDR5 also expressed eGFP. Binding of immune sera to D2F2-mDR5/GFP cells with green fluorescence indicated the presence of anti-mDR5 Ab. Anti-mDR5 mAb MD5-1 was the positive control binding 100% of the cells which expressed the transgene. At 1:20 dilution, DR5 immune sera bound 2, 7, 31, and 37% of DR5/eGFP positive cells following one, two, three and four DNA vaccinations, respectively. Electro-vaccination with heterologous human or rat DR5 DNA did not induce anti-mDR5 Ab. To test anti-tumor activity, BALB/c mice electro-vaccinated with pmDR5ectm-Td1 and pGM-CSF four to five times following Treg depletion were challenged s.c. with mammary tumors D2F2 or TUBO. Both tumor lines expressed endogenous mDR5 at modest levels. Approximately 30% of immunized mice were protected from the challenge suggesting that anti-mDR5 Ab induced by DNA vaccination may inhibit tumor growth. Because TRAIL is also implicated in mediating immune surveillance and thymocyte apoptosis and DR5 expression is upregulated upon T cell activation, tumor rejection by pmDR5 vaccination may occur via indirect T cell modulation as well as direct killing of tumor cells. Further investigation of the mechanism will provide necessary insight to enhance DR5 Ab response and combine DR5 vaccination with conventional therapies. (CA76340 and DOD W81XWH-07-1-0521)