tbuckley/cabot-search huggingface dataset:
Selective Insensitivity of ZR-75-1 Human Breast Cancer Cells to 2-Methoxyestradiol: Evidence for Type II 17β-Hydroxysteroid Dehydrogenase as the Underlying Cause
Authors: Zhi-Jian Liu, Won Jun Lee, Bao Ting Zhu
Journal: Cancer Research (2005)

Abstract 2-Methoxyestradiol (2-MeO-E2), a nonpolar endogenous metabolite of 17β-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions. Among the four human breast cancer cell lines tested (MCF-7, T-47D, ZR-75-1, and MDA-MB-435s), the ZR-75-1 cells were selectively insensitive to the antiproliferative actions of 2-MeO-E2, although these cells had a similar sensitivity as other cell lines to several other anticancer agents (5-fluorouracil, mitomycin C, doxorubicin, colchicine, vinorelbine, and paclitaxel). Mechanistically, this insensitivity is largely attributable to the presence of high levels of a steroid-selective metabolizing enzyme, the type II 17β-hydroxysteroid dehydrogenase (17β-HSD), in the ZR-75-1 cells, which rapidly converts 2-MeO-E2 to the inactive 2-methoxyestrone, but this enzyme does not metabolically inactivate other nonsteroidal anticancer agents. The type II 17β-HSD–mediated conversion of 2-MeO-E2 to 2-methoxyestrone in ZR-75-1 cells followed the first-order kinetics, with a very short half-life (∼2 hours). In comparison, the T-47D, MCF-7, and MDA-MB-435s human breast cancer cells, which were highly sensitive to 2-MeO-E2, had very low or undetectable catalytic activity for the conversion of 2-MeO-E2 to 2-methoxyestrone. Reverse transcription-PCR analysis of the mRNA levels of three known oxidative 17β-HSD isozymes (types II, IV, and VIII) revealed that only the type II isozyme was selectively expressed in the ZR-75-1 cells, whereas the other two isozymes were expressed in all four cell lines. Taken together, our results showed, for the first time, that the high levels of type II 17β-HSD present in ZR-75-1 cells were largely responsible for the facile conversion of 2-MeO-E2 to 2-methoxyestrone and also for the selective insensitivity to the antiproliferative actions of 2-MeO-E2.
Frank Howard Beddow
Authors: R. S. Ahearn
Journal: BMJ (2015)

Frank Howard Beddow was born in Yorkshire, but his family moved to the Wirral when he was a child. He was educated at Birkenhead School, where he considered a career in engineering but eventually chose medicine. After house officer positions and two years in the army, he embarked on training in orthopaedics in Liverpool, which was a renowned centre in the subject. Having completed his training he was appointed consultant at Whiston Hospital. Some years later he transferred to the Liverpool Royal Infirmary and, finally, in 1978, on …
BK virus-specific T cells for immunotherapy of progressive multifocal leukoencephalopathy: an open-label, single-cohort pilot study
Authors: Irene Cortese, Erin S Beck, Omar Al-Louzi, Joan Ohayon, Frances Andrada, Ikesinachi Osuorah, Jenifer Dwyer, B Jeanne Billioux, Nigar Dargah-zada, Matthew K Schindler, Kyle Binder, Lauren Reoma, Gina Norato, Yoshimi Enose-Akahata, Bryan R Smith, Maria Chiara Monaco, Eugene O Major, Steven Jacobson, David Stroncek, Steven Highfill, Sandhya Panch, Daniel S Reich, John Barrett, Avindra Nath, Pawel Muranski
Journal: The Lancet Neurology (2021)
Near-infrared light triggered multi-hit therapeutic nanosystem for tumor specific photothermal effect amplified signal pathway regulation and ferroptosis
Authors: He Lian, Ping Guan, Hongyan Tan, Xiaoshu Zhang, Zhaoxu Meng
Journal: Bioactive Materials (2021)

The high therapeutic resistance of tumor is the primary cause behind tumor recurrence and incurability. In recent years, scientists have devoted themselves to find a variety of treatments to solve this problem. Herein, we propose a multi-hit strategy that is based on the biodegradable hollow mesoporous Prussian blue (HMPB)-based nanosystem for tumor-specific therapy that encapsulated the critical heat shock protein 90 (HSP90) inhibitor 17-dimethylamino-ethylamino-17-demethoxydeldanamycin (17-DMAG). The nanosystem was further modified using thermotropic phase transition material star-PEG-PCL (sPP) and hyaluronic acid (HA), which offers near infrared light (NIR) responsive release characteristic, as well as enhanced tumor cell endocytosis. Upon cell internalization of 17-DMAG-HMPB@sPP@HA and under 808 nm laser irradiation, photothermal-conversion effect of HMPB directly kills cells using hyperthermia, which further causes phase transition of sPP to trigger release of 17-DMAG, inhibits HSP90 activity and blocks multiple signaling pathways, including cell cycle, Akt and HIF pathways. Additionally, the down-regulation of GPX4 protein expression by 17-DMAG and the release of ferric and ferrous ions from gradual degradation of HMPB in the endogenous mild acidic microenvironment in tumors promoted the occurrence of ferroptosis. Importantly, the antitumor effect of 17-DMAG and ferroptosis damage were amplified using photothermal effect of HMPB by accelerating release of ferric and ferrous ions, and reducing HSP90 expression in cells, which induced powerful antitumor effect in vitro and in vivo. This multi-hit therapeutic nanosystem helps provide a novel perspective for solving the predicament of cancer treatment, as well as a promising strategy for design of a novel cancer treatment nanoplatform.
P29-4 An exploratory study of challenges to delivering palliative care from the time of cancer diagnosis
Authors: Hisashi Suyama, Hiroshi Sunada, Yu Uneno, Yoshiki Horie, Akemi Naito, Shunsuke Oyamada, Junko Nozato, Yasuyuki Kojima, Masanori Mori, Takako Nakajima, Chikako Shimizu, Tatsuya Morita, Satoru Tsuneto, Manabu Muto
Journal: Annals of Oncology (2021)
Abstract 16517: G Beta Gamma Independent Role Of GRK2 in TNF Alpha Induced Beta-AR Dysfunction
Authors: Neelakantan T Vasudevan, Maradumane L Mohan, Manveen K Gupta, Elizabeth E Martelli, David Young, Arthur M Feldman, Subha Sen, Sathyamangla V Naga Prasad
Journal: Circulation (2011)

Cytokines contribute to left ventricular dysfunction and cardiomyopathy by altering cardiac mechanical function by negative inotropic effects. Although cytokine-induced β-adrenergic receptor (βAR) ...
STRONG: metagenomics strain resolution on assembly graphs
Authors: Christopher Quince, Sergey Nurk, Sebastien Raguideau, Robert James, Orkun S. Soyer, J. Kimberly Summers, Antoine Limasset, A. Murat Eren, Rayan Chikhi, Aaron E. Darling
Journal: Genome biology (2021)

Abstract We introduce STrain Resolution ON assembly Graphs (STRONG), which identifies strains de novo, from multiple metagenome samples. STRONG performs coassembly, and binning into metagenome assembled genomes (MAGs), and stores the coassembly graph prior to variant simplification. This enables the subgraphs and their unitig per-sample coverages, for individual single-copy core genes (SCGs) in each MAG, to be extracted. A Bayesian algorithm, BayesPaths, determines the number of strains present, their haplotypes or sequences on the SCGs, and abundances. STRONG is validated using synthetic communities and for a real anaerobic digestor time series generates haplotypes that match those observed from long Nanopore reads.
Multifunctional Dressing for Wound Diagnosis and Rehabilitation
Authors: Ning Tang, Youbin Zheng, Daxiang Cui, Hossam Haick
Journal: Advanced Healthcare Materials (2021)

A wound dressing is a sterile pad or compress that is used in direct contact with a wound to help it heal and prevent further issues or complications. Though wound healing is an intricate dynamic process that involves multiple biomolecular species, conventional wound dressings have a limited ability to provide timely information of abnormal conditions, missing the best time for early treatment. The current perspective presents and discusses the design and development of smart wound dressings that are integrated with multifunctional materials, wearable sensors and drug delivery systems as well as their application ranging from wound monitoring to timely application of therapeutics. The perspective also discusses the ongoing challenges and exciting opportunities associated with the development of wearable sensor-based smart wound dressing and provide critical insights into wound healing monitoring and management.
ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors
Authors: Ana Portelinha, Scott Thompson, Roger A. Smith, Mariana Da Silva Ferreira, Zahra Asgari, Andrea Knezevic, Venkatraman Seshan, Elisa de Stanchina, Sandeep Gupta, Louis Denis, Anas Younes, Sanjeeva Reddy
Journal: Cell Reports Medicine (2021)
PD3-1-3 Utility and role of multigene panel tests for patients with cancer: Retrospective data from a single institution
Authors: Yuya Hirasawa, Masaharu Aga, Naoto Aiko, Yusuke Hamakawa, Kazuhito Miyazaki, Yuri Taniguchi, Yuki Misumi, Yoko Agemi, Mari Ishii, Tsuneo Shimokawa, Hiroaki Okamoto
Journal: Annals of Oncology (2021)
Discovery of Small Molecule Bak Activator for Lung Cancer Therapy
Authors: Dongkyoo Park, Abu Syed Md Anisuzzaman, Andrew T. Magis, Guo Chen, Maohua Xie, Guojing Zhang, Madhusmita Behera, Gabriel L. Sica, Suresh S. Ramalingam, Taofeek K. Owonikoko, Xingming Deng
Journal: Theranostics (2021)

Rationale: Bak is a major proapoptotic Bcl2 family member and a required molecule for apoptotic cell death.High levels of endogenous Bak were observed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines.Increased Bak expression was correlated with poor prognosis of NSCLC patients, suggesting that Bak protein is an attractive target for lung cancer therapy.The BH3 domain functions as death domain and is required for Bak to initiate apoptotic cell death.Thus, the BH3 domain is attractive target for discovery of Bak agonist.Methods: The BH3 death domain binding pocket (aa75-88) of Bak was chosen as a docking site for screening of small molecule Bak activators using the UCSF DOCK 6.1 program suite and the NCI chemical library (300,000 small molecules) database.The top 500 compounds determined to have the highest affinity for the BH3 domain were obtained from the NCI and tested for cytotoxicity for further screening.We identified a small molecule Bak activator BKA-073 as the lead compound.The binding affinity of BKA-073 with Bak protein was analyzed by isothermal titration calorimetry (ITC) assay.BKA-073-mediated Bak activation via oligomerization was analyzed by a cross-linking with Bis (maleimido) hexane (BMH).Sensitivity of BKA-073 to lung cancer cells in vitro was evaluated by dynamic BH3 profiling (DBP) and apoptotic cell death assay.The potency of BKA-073 alone or in combination with radiotherapy or Bcl2 inhibitor was evaluated in animal models.Results: We found that BKA-073 binds Bak at BH3 domain with high affinity and selectivity.BKA-073/Bak binding promotes Bak oligomerization and mitochondrial priming that activates its proapoptotic function.BKA-073 potently suppresses tumor growth without significant normal tissue toxicity in small cell lung cancer (SCLC) and NSCLC xenografts, patient-derived xenografts, and genetically engineered mouse models of mutant KRAS-driven cancer.Bak accumulates in radioresistant lung cancer cells and BKA-073 reverses radioresistance.Combination of BKA-073 with Bcl-2 inhibitor venetoclax exhibits strong synergy against lung cancer in vivo.Conclusions: Development of small molecule Bak activator may provide a new class of anticancer agents to treat lung cancer.
Principles of Genomic Newborn Screening Programs
Authors: Lilian Downie, Jane Halliday, Sharon Lewis, David J. Amor
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Genomic newborn screening (gNBS) may optimize the health and well-being of children and families. Screening programs are required to be evidence based, acceptable, and beneficial. <h3>Objectives</h3> To identify what has been discovered following the reporting of the first gNBS pilot projects and to provide a summary of key points for the design of gNBS. <h3>Evidence Review</h3> A systematic literature review was performed on April 14, 2021, identifying 36 articles that addressed the following questions: (1) what is the interest in and what would be the uptake of gNBS? (2) what diseases and genes should be included? (3) what is the validity and utility of gNBS? and (4) what are the ethical, legal, and social implications? Articles were only included if they generated new evidence; all opinion pieces were excluded. <h3>Findings</h3> In the 36 articles included, there was high concordance, except for gene disease inclusion, which was highly variable. Key findings were the need for equitable access, appropriate educational materials, and informed and flexible consent. The process for selecting genes for testing should be transparent and reflect that parents value the certainty of prediction over actionability. Data should be analyzed in a way that minimizes uncertainty and incidental findings. The expansion of traditional newborn screening (tNBS) to identify more life-threatening and treatable diseases needs to be balanced against the complexity of consenting parents of newborns for genomic testing as well as the risk that overall uptake of tNBS may decline. The literature reflected that the right of a child to self-determination should be valued more than the possibility of the whole family benefiting from a newborn genomic test. <h3>Conclusions and Relevance</h3> The findings of this systematic review suggest that implementing gNBS will require a nuanced approach. There are gaps in our knowledge, such as the views of diverse populations, the capabilities of health systems, and health economic implications. It will be essential to rigorously evaluate outcomes and ensure programs can evolve to maximize benefit.
Association of lung clearance index with survival in individuals with cystic fibrosis
Authors: Johanna Manuela Kurz, Kathryn Angela Ramsey, Romy Rodriguez, Ben Spycher, Reta Fischer Biner, Philipp Latzin, Florian Singer
Journal: European Respiratory Journal (2021)

Background The lung clearance index (LCI) assesses global ventilation inhomogeneity and is a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease. We examined the association of LCI with the risk of death or lung transplantation (LTx) in individuals with CF. Methods We performed a retrospective analysis in a cohort of individuals with CF aged ≥5 years with LCI and forced expired volume in 1 s (FEV 1 ) measurements performed between 1980 and 2006. The outcome was time until death or LTx. We used the earliest available LCI and FEV 1 values in a Cox proportional hazards regression adjusted for demographic and clinical variables. For sensitivity analyses, we used the mean of the first three LCI and FEV 1 measurements, stratified the cohort based on age, and investigated individuals with normal FEV 1 . Results In total, 237 individuals with CF with a mean (range) age of 13.9 (5.6–41.0) years were included. The time-to-event analysis accrued 3813 person-years and 94 (40%) individuals died or received LTx. Crude hazard ratios were 1.04 (95% CI 1.01–1.06) per 1.0 z-score increase in LCI and 1.25 (95% CI 1.11–1.41) per 1.0 z-score decrease in FEV 1 . After adjusting LCI and FEV 1 mutually in addition to sex, age, body mass index and number of hospitalisations, hazard ratios were 1.04 (95% CI 1.01–1.07) for LCI and 1.12 (95% CI 0.95–1.33) for FEV 1 . Sensitivity analyses yielded similar results and using the mean LCI strengthened the associations. Conclusions Increased ventilation inhomogeneity is associated with greater risk of death or LTx. Our data support LCI as novel surrogate of survival in individuals with CF.
O-15 Randomized, phase 3 study of second-line tislelizumab vs chemotherapy in advanced or metastatic esophageal squamous cell carcinoma (RATIONALE 302) in the overall population and Europe/North America subgroup
Authors: J. Ajani, F. El Hajbi, D. Cunningham, M. Alsina, P. Thuss-Patience, G. Scagliotti, M. Van den Eynde, I. Rybkin, L. Shen, K. Kato, S. Kim, S. D’Alonzo, W. Yu, A. Tao, E. Van Cutsem
Journal: Annals of Oncology (2021)
Reversibly immortalized keratinocytes (iKera) facilitate re-epithelization and skin wound healing: Potential applications in cell-based skin tissue engineering
Authors: Jiamin Zhong, Hao Wang, Ke Yang, Huifeng Wang, Chongwen Duan, Na Ni, Liqin An, Yetao Luo, Piao Zhao, Yannian Gou, Shiyan Sheng, Deyao Shi, Connie Chen, William Wagstaff, Bryce Hendren-Santiago, Rex C. Haydon, Hue H. Luu, Russell R. Reid, Sherwin H. Ho, Guillermo A. Ameer, Le Shen, Tong-Chuan He, Jiaming Fan
Journal: Bioactive Materials (2021)

Skin injury is repaired through a multi-phase wound healing process of tissue granulation and re-epithelialization. Any failure in the healing process may lead to chronic non-healing wounds or abnormal scar formation. Although significant progress has been made in developing novel scaffolds and/or cell-based therapeutic strategies to promote wound healing, effective management of large chronic skin wounds remains a clinical challenge. Keratinocytes are critical to re-epithelialization and wound healing. Here, we investigated whether exogenous keratinocytes, in combination with a citrate-based scaffold, enhanced skin wound healing. We first established reversibly immortalized mouse keratinocytes (iKera), and confirmed that the iKera cells expressed keratinocyte markers, and were responsive to UVB treatment, and were non-tumorigenic. In a proof-of-principle experiment, we demonstrated that iKera cells embedded in citrate-based scaffold PPCN provided more effective re-epithelialization and cutaneous wound healing than that of either PPCN or iKera cells alone, in a mouse skin wound model. Thus, these results demonstrate that iKera cells may serve as a valuable skin epithelial source when, combining with appropriate biocompatible scaffolds, to investigate cutaneous wound healing and skin regeneration.
SARS-CoV-2 Vaccine Effectiveness in a High-Risk National Population in a Real-World Setting
Authors: Adeel A. Butt, Saad B. Omer, Peng Yan, Obaid S. Shaikh, Florian B. Mayr
Journal: Annals of Internal Medicine (2021)

With the emergency use authorization of multiple vaccines against SARS-CoV-2 infection, data are urgently needed to determine their effectiveness in a real-world setting.To evaluate the short-term effectiveness of vaccines in preventing SARS-CoV-2 infection.Test-negative case-control study using conditional logistic regression.U.S. Department of Veterans Affairs health care system.All veterans who had testing for SARS-CoV-2 infection between 15 December 2020 and 4 March 2021 and no confirmed infection before 15 December 2020.SARS-CoV-2 vaccination with either the BNT-162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine as part of routine clinical care.Effectiveness of vaccination against confirmed SARS-CoV-2 infection.Among 54 360 persons who tested positive and 54 360 propensity score-matched control participants, the median age was 61 years, 83.6% were male, and 62% were White. Median body mass index was 31 kg/m2 among those who tested positive and 30 kg/m2 among those who tested negative. Among those who tested positive, 9800 (18.0%) had been vaccinated; among those who tested negative, 17 825 (32.8%) had been vaccinated. Overall vaccine effectiveness 7 or more days after the second dose was 97.1% (95% CI, 96.6% to 97.5%). Effectiveness was 96.2% (CI, 95.5% to 96.9%) for the Pfizer-BioNTech BNT-162b2 vaccine and 98.2% (CI, 97.5% to 98.6%) for the Moderna mRNA-1273 vaccine. Effectiveness remained above 95% regardless of age group, sex, race, or presence of comorbidities.Predominantly male population; lack of data on disease severity, mortality, and effectiveness by SARS-CoV-2 variants of concern; and short-term follow-up.Currently used vaccines against SARS-CoV-2 infection are highly effective in preventing confirmed infection in a high-risk population in a real-world setting.None.
Rethinking Cancer Clinical Trial Conduct Induced by COVID-19: An Academic Center, Industry, Government, and Regulatory Agency Perspective
Authors: Keith T. Flaherty, James H. Doroshow, Susan Galbraith, Antoni Ribas, Paul G. Kluetz, Richard Pazdur, Marc R. Theoret
Journal: Cancer Discovery (2021)

Abstract Summary: The COVID-19 pandemic brought about major changes in cancer clinical trials. In its aftermath, the community has an opportunity to incorporate some of these changes as part of the future of trial conduct to make it more patient centered.
Maternal obesity increases the risk and severity of NAFLD in offspring
Authors: Hannes Hagström, Tracey G. Simon, Bjorn Roelstraete, Olof Stephansson, Jonas Söderling, Jonas F. Ludvigsson
Journal: Journal of Hepatology (2021)

Maternal obesity has been linked to the development of cardiovascular disease and diabetes in offspring, but its relationship to non-alcoholic fatty liver disease (NAFLD) is unclear.Through the nationwide ESPRESSO cohort study we identified all individuals ≤25 years of age in Sweden with biopsy-verified NAFLD diagnosed between 1992 and 2016 (n = 165). These were matched by age, sex, and calendar year with up to 5 controls (n = 717). Through linkage with the nationwide Swedish Medical Birth Register (MBR) we retrieved data on maternal early-pregnancy BMI, and possible confounders, in order to calculate adjusted odds ratios (aORs) for NAFLD in offspring.Maternal BMI was associated with NAFLD in offspring: underweight (aOR 0.84; 95% CI 0.14-5.15), normal weight (reference, aOR 1), overweight (aOR 1.51; 0.95-2.40), and obese (aOR 3.26; 1.72-6.19) women. Severe NAFLD (biopsy-proven fibrosis or cirrhosis) was also more common in offspring of overweight (aOR 1.94; 95% CI 0.96-3.90) and obese (aOR 3.67; 95% CI 1.61-8.38) mothers. Associations were similar after adjusting for maternal pre-eclampsia and gestational diabetes. Socio-economic parameters (smoking, mother born outside the Nordic countries and less than 10 years of basic education) were also associated with NAFLD in offspring but did not materially alter the effect size of maternal BMI in a multivariable model.This nationwide study found a strong association between maternal overweight/obesity and future NAFLD in offspring. Adjusting for socio-economic and metabolic parameters in the mother did not affect this finding, suggesting that maternal obesity is an independent risk factor for NAFLD in offspring.In a study of all young persons in Sweden with a liver biopsy consistent with fatty liver, the authors found that compared to matched controls, the risk of fatty liver was much higher in those with obese mothers. This was independent of available confounders and suggests that the high prevalence of obesity in younger persons might lead to a higher risk of fatty liver in their offspring.
Transplant Biopsy Assessment in 21st Century
Authors: Andrew F. Malone
Journal: Journal of the American Society of Nephrology (2021)

The Achilles heel of solid organ transplantation is the alloimmune reaction to foreign tissue, or rejection. Two tools, serum creatinine and biopsy histology, are traditionally used to assess for allograft function, viability, and rejection. Our u nderstanding of rejection is based on histologic