tbuckley/cabot-search huggingface dataset:
Noninvasive imaging of Hypoxia-inducible Factor 1α (HIF-1α) level during radiation therapy of cancer
Authors: Fang Li, Pierre Sonveaux, Mark W. Dewhirst, Chuan-Yuan Li
Journal: Cancer Research (2005)

5267  Background and Rationale - Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor involved in tumor angiogenesis, metastasis, and tumor resistance to therapy. More particularly, HIF-1α activation has been shown to participate in tumor regrowth after radiotherapy. The level of HIF-1α is regulated in an oxygen-dependent manner, i.e., the protein is stabilized under hypoxia. There is a strong interest in understanding the regulation of HIF-1α in tumor cells for understanding cancer biology and tumor response to treatment. A non-invasive approach to observe the level of HIF-1α in vivo would be especially desirable since it would allow the investigation of its regulation during tumor growth and under various treatment conditions. Experimental Approach - To image the level of HIF-1α, we took advantage of the fact that the oxygen-dependent regulation of HIF-1α is exclusively mediated by its oxygen dependent domain (ODD). We engineered a novel ODD-luciferase gene in which the ODD domain was fused with a firefly luciferase reporter gene. We reasoned that the level of the fusion protein and its luminescence would be regulated by the oxygen tension in host cells and could thus be imaged non-invasively as a HIF-1α and oxygen reporter. Results - The oxygen-dependent status of ODD-luciferase was first evaluated in tissue culture experiments. In 4T1 tumor cells stably transfected with the fusion reporter gene, we observed no background level of luminescence. However, when the cells were exposed to hypoxia, hypoxia-mimic CoCl2, or proteasome inhibitor LLnV, the luciferase activity increased by about 4, 44 and 28-fold respectively. We then inoculated the cells subcutaneously in nude mice, and clearly observed ODD-luciferase activity when the tumors reached 3-5 mm in diameter. ODD-luciferase activity was also visible in metastatic tumors arising from intravenous tumor cell injection. After the demonstration of the sensitivity of our model to image tumor hypoxia, we further analyzed the changes in ODD-luciferase activity in tumors treated with clinically-relevant doses of ionizing radiations. We observed a significant increase in the level of ODD-luciferase activity starting from 3 days after irradiation. In contrast, irradiated tumors expressing a control CMV-luciferase construct showed no change in luciferase activity. Together, these results have clear implications for radiation treatment (oxygen sensor) and tumor angiogenic response (HIF-1α reporter). Conclusions - Our ODD-luciferase fusion reporter gene model provides a useful tool to non-invasively image HIF-1α protein levels and/or tumor hypoxia in vivo. It may constitute an easy-to-use and highly sensitive approach to study how tumors respond to treatments and for evaluating novel anti-HIF1-α therapeutics.
Rapamycin prevents the impairments of social recognition induced by anti-P antibody in a murine model
Authors: Xuejiao Wang, Pingting Yang, Ling Qin
Journal: Annals of the Rheumatic Diseases (2019)

The antiribosomal P antibody (anti-P) is detected predominantly in patients with systemic lupus erythematosus (SLE)1 and associated with a variety of neuropsychiatric manifestations (psychosis, mood disorders, cognitive decline, seizures and aseptic meningitis).2 3 A causal link between anti-P and the neuropsychiatric problems remains to be verified. Recently, anti-P has increasingly been associated with memory impairments. By passive transfer of anti-P into the brain of animals, previous experiments have revealed that hippocampus neurons are prime targets of anti-P, and spatial memory is impaired by the transferred anti-P.4 5 However, it remains unknown whether anti-P affects on the social memory (the memory of familiar conspecifics). Recently, the ventral CA1 region of hippocampus (vCA1) has been found to play a necessary and sufficient role in social memory.6 We, therefore, directly injected anti-P IgG (1.7 mg/mL, 0.5 µL) isolated from SLE patient sera, or control IgG from normal individuals or vehicle (artificial cerebrospinal fluid) …
Combining teledermatology with nonphysician members of the health care team to address access and compliance barriers in pediatric atopic dermatitis: A needs assessment
Authors: Arianne S. Kourosh, Lynda Schneider, Elena B. Hawryluk, Lana X. Tong, Corinna J. Rea, Joseph Kvedar
Journal: Journal of the American Academy of Dermatology (2019)
Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models
Authors: Lucia Nappi, Adeleke H. Aguda, Nader Al Nakouzi, Barbara Lelj-Garolla, Eliana Beraldi, Nada Lallous, Marisa Thi, Susan Moore, Ladan Fazli, Dulguun Battsogt, Sophie Stief, Fuqiang Ban, Nham T. Nguyen, Neetu Saxena, Evgenia Dueva, Fan Zhang, Takeshi Yamazaki, Amina Zoubeidi, Artem Cherkasov, Gary D. Brayer, Martin Gleave
Journal: Journal of Clinical Investigation (2019)

HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly disordered structure challenges rational structure-guided drug discovery. We performed multistep biochemical, structural, and computational experiments to define a spherical 24-monomer complex composed of 12 HSP27 dimers with a phosphorylation pocket flanked by serine residues between their N-terminal domains. Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. Ivermectin potentiated activity of anti–androgen receptor and anti-EGFR drugs in prostate and EGFR/HER2-driven tumor models, respectively, identifying a repurposing approach for cotargeting stress-adaptive responses to overcome resistance to inhibitors of oncogenic pathway signaling.
Efficacy, rate of tumor response, and safety of a short course (12-24 weeks) of oral vismodegib in various histologic subtypes (infiltrative, nodular, and superficial) of high-risk or locally advanced basal cell carcinoma, in an open-label, prospective case series clinical trial
Authors: Scott W. Fosko, Melinda B. Chu, Eric Armbrecht, Tim Galperin, Geoffrey A. Potts, Adam Mattox, Anastasia Kurta, Kristen Polito, Jordan B. Slutsky, Nicole M. Burkemper, M. Yadira Hurley
Journal: Journal of the American Academy of Dermatology (2019)
We are failing to improve the evidence base for ‘exercise referral’: how a physical activity referral scheme taxonomy can help
Authors: Coral L Hanson, Emily J Oliver, Caroline J Dodd-Reynolds, Paul Kelly
Journal: British Journal of Sports Medicine (2019)

Increasing physical activity (PA) is a global public health priority.1 For decades, exercise referral schemes (ERS) have been a popular way for healthcare professionals in primary and secondary care to help patients increase their PA.

Delivery of ERS varies widely, with the construction of an evidence base informing ‘what works best’ limited by a lack of understanding about what individual schemes deliver and how.2 Between-scheme analyses are extremely challenging due to varying quality of reporting (eg, of scheme delivery components and processes) and evaluations.3 4 As a consequence, overviews of ERS evidence5 6 are flawed by combining heterogeneous interventions (eg, falls prevention via physiotherapist referral and hypertension management via general practitioner (GP) referral) and datasets.

Collectively, the underwhelming findings of such overviews lead to concerns over commissioning ERS, and the inability of national policy and best practice guidelines to recommend a ‘gold standard’ structure, or even comment on ‘what good looks like’.5 We do not know whether local tailoring of ERS is more effective and efficient than a standardised approach.

To advance knowledge …
Esophageal Adenocarcinoma With Subscalp Metastasis as the First Manifestation Detected by 18F-FDG PET/CT
Authors: Tingting Xu, Xinyi Zhang, Wenhui Fu, Chengrun Zeng, Yue Chen
Journal: Clinical Nuclear Medicine (2019)

Subscalp metastases occur infrequently in malignant tumors but may appear as an initial clinical presentation. This report presents the case of a 53-year-old man who recently found a painless nodule under the right side of his scalp. F-FDG PET/CT, endoscopy, and tissue biopsy diagnosed the nodule as a metastasis of esophageal adenocarcinoma.
Reply to Xuefeng Liu’s Letter to the Editor, re: Kimmo Kettunen, Peter J. Boström, Tarja Lamminen, et al. Personalized Drug Sensitivity Screening for Bladder Cancer Using Conditionally Reprogrammed Patient-derived Cells. Eur Urol 2019;76:430–4: Can Patient-derived Cancer Models Change the Costliest Cancer Type?
Authors: Kimmo Kettunen, Peter Boström, Pekka Taimen
Journal: European Urology (2019)
Quantifying the benefit offered by transcript assembly with Scallop-LR on single-molecule long reads
Authors: Laura H. Tung, Mingfu Shao, Carl Kingsford
Journal: Genome biology (2019)

Single-molecule long-read sequencing has been used to improve mRNA isoform identification. However, not all single-molecule long reads represent full transcripts due to incomplete cDNA synthesis and sequencing length limits. This drives a need for long-read transcript assembly. By adding long-read-specific optimizations to Scallop, we developed Scallop-LR, a reference-based long-read transcript assembler. Analyzing 26 PacBio samples, we quantified the benefit of performing transcript assembly on long reads. We demonstrate Scallop-LR identifies more known transcripts and potentially novel isoforms for the human transcriptome than Iso-Seq Analysis and StringTie, indicating that long-read transcript assembly by Scallop-LR can reveal a more complete human transcriptome.
Adding Azathioprine and Hydroxyurea Preconditioning to Alemtuzumab/TBI May Improve Donor Chimerism in Matched Sibling Donor Allogeneic Stem Cell Transplantation in Adult Sickle Cell Patients
Authors: Erfan Nur, Sacha S Zeerleder, Aafke E. Gaartman, Caroline E Rutten, Charlotte F.J. Van Tuijn, Liesbeth E.M. Suijk, Mette D Hazenberg, Bart J. Biemond
Journal: Blood (2019)
Magnetic Resonance Imaging With Extracellular Contrast Detects Hepatocellular Carcinoma With Greater Accuracy Than With Gadoxetic Acid or Computed Tomography
Authors: Ji Hye Min, Jong Man Kim, Young Kon Kim, Dong Ik Cha, Tae Wook Kang, Honsoul Kim, Gyu Seong Choi, Seo-Youn Choi, Soohyun Ahn
Journal: Clinical Gastroenterology and Hepatology (2019)
A phase 1 multiple-dose safety, pharmacokinetic, and pharmacodynamic Study of PTC299, a novel VEGF expression inhibitor for treatment of solid tumors
Authors: Samit Hirawat, Gary Elfring, Valerie Northcutt, Nicolas Paquette-Lamontagne, Thomas Davis, Marla Weetall, Langdon Miller
Journal: Cancer Research (2007)

924  BACKGROUND: VEGF expression is highly regulated posttranscriptionally through the 59- and 39-untranslated regions (UTRs) of its mRNA. PTC299 is a novel, orally bioavailable, small molecule designed to act through the VEGF 59-UTR to inhibit tumor VEGF production. In multiple preclinical human tumor xenograft models, PTC299 reduces tumor and circulating plasma VEGF concentrations, decreases tumor microvessel density, and substantially slows tumor growth. When given together with cytotoxic agents or with other antiangiogenics, PTC299 enhances tumor growth delay. In a single-dose study in human healthy volunteers, PTC299 was well tolerated through the highest dose administered (3 mg/kg). Plasma concentrations active in preclinical models were achieved.  METHODS AND MATERIALS: This Phase 1, randomized, double-blind, placebo-controlled, escalating multiple-dose study in healthy adult volunteers has evaluated oral PTC299 treatment given twice per day (BID) for 7 days to determine PTC299 safety, PK profile, and effects on plasma and serum VEGF levels; subjects have been followed with clinical observations, safety laboratory testing, and frequent plasma sampling over the dosing period and also at 7 and 14 days after the last PTC299 dose.  RESULTS: 8 subjects (3 PTC299, 1 placebo per gender) have been enrolled at each of 3 progressively higher dose levels on a BID schedule, for a total of 24 subjects (12 males, 12 females; median age 46 [range, 21-64] years). PTC299 has been well tolerated with no serious, dose-limiting, or definitively drug-related adverse events. PK data indicates dose proportional increases in plasma exposures with an accumulation in Cmax and AUC0-24 of ~2-fold over 7 days. The target trough plasma concentration has been maintained at all dose levels with the highest dose tested achieving a mean trough plasma concentration ~5 times the target plasma concentration at 12 hours after the final PTC299 dose. Additional accrual to evaluate PTC299 doses given 3 times per day is currently ongoing.  CONCLUSIONS: PTC299 is the first drug specifically designed to modulate post-transcriptional control mechanisms to treat human disease. In this initial, multiple-dose clinical study, PTC299 shows safety at plasma exposures associated with preclinical activity. Final clinical data on dose ranging, safety, PK, and plasma/serum VEGF levels will be presented at the meeting. PK modeling will be used to project an appropriate dosing regimen for subsequent studies in cancer patients.
Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation
Authors: Hannah Gelman, Jennifer N. Dines, Jonathan Berg, Alice H. Berger, Sarah Brnich, Fuki M. Hisama, Richard G. James, Alan F. Rubin, Jay Shendure, Brian Shirts, Douglas M. Fowler, Lea M. Starita
Journal: Genome Medicine (2019)

Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously, are increasingly generating data that can be used as additional evidence for or against variant pathogenicity. Such assays have the potential to resolve variants of uncertain significance, thereby increasing the clinical utility of genomic testing. Existing standards from the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) and new guidelines from the Clinical Genome Resource (ClinGen) establish the role of functional data in variant interpretation, but do not address the specific challenges or advantages of using functional data derived from multiplexed assays. Here, we build on these existing guidelines to provide recommendations to experimentalists for the production and reporting of multiplexed functional data and to clinicians for the evaluation and use of such data. By following these recommendations, experimentalists can produce transparent, complete, and well-validated datasets that are primed for clinical uptake. Our recommendations to clinicians and diagnostic labs on how to evaluate the quality of multiplexed functional datasets, and how different datasets could be incorporated into the ACMG/AMP variant-interpretation framework, will hopefully clarify whether and how such data should be used. The recommendations that we provide are designed to enhance the quality and utility of multiplexed functional data, and to promote their judicious use.
An Invited Commentary on “Does saphenous vein graft failure even matter? Commentary on: Mid-term and long-term outcomes of endoscopic versus open vein harvesting for coronary artery bypass: A systematic review and meta-analysis” (Int J Surg 2019;72:167–173)
Authors: Ajita Naik, Irbaz Hameed, Mario Gaudino
Journal: International Journal of Surgery (2019)
A home-made method to remove an SX-Ella Danis stent
Authors: Yu-Jen Chen, Ming-Chih Hou
Journal: Endoscopy (2019)

A 48-year-old man with alcoholic liver cirrhosis, Child-Pugh score A(6), became ill when on a business trip to Copenhagen, Denmark. Massive hematemesis and severe hepatic encephalopathy occurred, and he underwent placement of an SX-Ella Danis covered stent (Ella-CS, Hradec Králové, Czech Republic) ([Fig. 1], [Fig. 2]) in a Danish hospital. After stabilization, he was transferred back to Taiwan – where no Ella extractor was available. The stent had now been in position for over 2 weeks. We used a polypectomy snare (Olympus SD-5U/6U-1) ([Fig. 3]) and a 50-cm-long tapered overtube (Cliny Inc., Japan) to successfully and smoothly remove the stent ([Video 1]).
Circular RNA Sequencing Identifies CircASAP1 as a Key Regulator in Hepatocellular Carcinoma Metastasis
Authors: Zhi‐Qiang Hu, Shao‐Lai Zhou, Jia Li, Zheng‐Jun Zhou, Peng‐Cheng Wang, Hao‐Yang Xin, Li Mao, Chu‐Bin Luo, Song‐Yang Yu, Xiao‐Wu Huang, Ya Cao, Jia Fan, Jian Zhou
Journal: Hepatology (2019)

There is growing evidence that single-stranded, circular RNA (circRNA) plays a key role in the development of certain cancers, including hepatocellular carcinoma (HCC). It is less clear, however, what role circRNA plays in HCC metastasis.In this study, through circRNA sequencing, we identified a circRNA: circASAP1 (a circRNA derived from exons 2 and 3 of the ASAP1 gene, hsa_circ_0085616), which is associated with pulmonary metastasis after curative resection in patients with HCC. CircASAP1 was overexpressed in HCC cell lines with high metastatic potential and in metastatic HCCs. In vitro, circASAP1 promoted cell proliferation, colony formation, migration, and invasion, and in vivo, it enhanced tumor growth and pulmonary metastasis. Mechanism studies showed that circASAP1 acts as a competing endogenous RNA for microRNA 326 (miR-326) and microRNA 532-5p (miR-532-5p), both of which are tumor suppressors in HCC. We found that mitogen-activated protein kinase (MAPK) 1 and colony stimulating factor (CSF)-1 were direct common targets for microRNA 326 (miR-326) and microRNA 532-5p (miR-532-5p), which were regulated by circASAP1. CircASAP1 promotes HCC cell proliferation and invasion by regulating miR-326/miR-532-5p-MAPK1 signaling and, furthermore, mediates tumor-associated macrophage infiltration by regulating the miR-326/miR-532-5p-CSF-1 pathway. Clinical HCC samples exhibited a positive correlation between circASAP1 expression and levels of CSF-1, MAPK1, and CD68+ tumor-associated macrophages, all of which were predictive of patient outcomes.We identified circASAP1 as a key regulator of HCC metastasis that acts on miR-326/miR-532-5p-MAPK1/CSF-1 signaling and serves as a prognostic predictor in patients with HCC.
Digital assessment of falls risk, frailty, and mobility impairment using wearable sensors
Authors: Barry R. Greene, Killian McManus, Stephen J. Redmond, Brian Caulfield, Charlene C. Quinn
Journal: npj Digital Medicine (2019)

Falls are among the most frequent and costly population health issues, costing $50bn each year in the US. In current clinical practice, falls (and associated fall risk) are often self-reported after the "first fall", delaying primary prevention of falls and development of targeted fall prevention interventions. Current methods for assessing falls risk can be subjective, inaccurate, have low inter-rater reliability, and do not address factors contributing to falls (poor balance, gait speed, transfers, turning). 8521 participants (72.7 ± 12.0 years, 5392 female) from six countries were assessed using a digital falls risk assessment protocol. Data consisted of wearable sensor data captured during the Timed Up and Go (TUG) test along with self-reported questionnaire data on falls risk factors, applied to previously trained and validated classifier models. We found that 25.8% of patients reported a fall in the previous 12 months, of the 74.6% of participants that had not reported a fall, 21.5% were found to have a high predicted risk of falls. Overall 26.2% of patients were predicted to be at high risk of falls. 29.8% of participants were found to have slow walking speed, while 19.8% had high gait variability and 17.5% had problems with transfers. We report an observational study of results obtained from a novel digital fall risk assessment protocol. This protocol is intended to support the early identification of older adults at risk of falls and inform the creation of appropriate personalized interventions to prevent falls. A population-based approach to management of falls using objective measures of falls risk and mobility impairment, may help reduce unnecessary outpatient and emergency department utilization by improving risk prediction and stratification, driving more patients towards clinical and community-based falls prevention activities.
Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics
Authors: Chongjin Zhong, Chao Jiang, Suiying Ni, Qizhi Wang, Lingge Cheng, Huan Wang, Qixiang Zhang, Wenyue Liu, Jingwei Zhang, Jiali Liu, Mulan Wang, Min Jin, Peiqiang Shen, Xuequan Yao, Guangji Wang, Fang Zhou
Journal: Acta Pharmaceutica Sinica B (2019)

Shenmai injection (SMI) is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer. Previously, we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors. However, the underlying mechanisms and bioactive constituents remained unknown. In the present work, the regulatory effects of SMI on tumor vasculature were determined, and the potential anti-angiogenic components targeting tumor endothelial cells (TECs) were identified. Multidimensional pharmacokinetic profiles of ginsenosides in plasma, subcutaneous tumors, and TECs were investigated. The results showed that the concentrations of protopanaxadiol-type (PPD) ginsenosides (Rb1, Rb2/Rb3, Rc, and Rd) in both plasma and tumors, were higher than those of protopanaxatriol-type (Rg1 and Re) and oleanane-type (Ro) ginsenosides. Among PPD-type ginsenosides, Rd exhibited the greatest concentrations in tumors and TECs after repeated injection. In vivo bioactivity results showed that Rd suppressed neovascularization in tumors, normalized the structure of tumor vessels, and improved the anti-tumor effect of 5-fluorouracil (5FU) in xenograft mice. Furthermore, Rd inhibited the migration and tube formation capacity of endothelial cells in vitro. In conclusion, Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.