tbuckley/cabot-search huggingface dataset:
ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy
Authors: Jared E Lopes, Jan L Fisher, Heather L Flick, Chunhua Wang, Lei Sun, Marc S Ernstoff, Juan C Alvarez, Heather C Losey
Journal: Journal for ImmunoTherapy of Cancer (2020)

Interleukin-2 (IL-2) plays a pivotal role in immune homeostasis due to its ability to stimulate numerous lymphocyte subsets including natural killer (NK) cells, effector CD4+ and CD8+ T cells, and regulatory T cells (Tregs). Low concentrations of IL-2 induce signaling through the high-affinity IL-2 receptor (IL-2R) comprised of IL-2Rα, IL-2Rβ, and common γ chain (γc), preferentially expressed on Tregs. Higher concentrations of IL-2 are necessary to induce signaling through the intermediate-affinity IL-2R, composed of IL-2Rβ and γc, expressed on memory CD8+ T cells and NK cells. Recombinant human IL-2 (rhIL-2) is approved for treatment of metastatic melanoma and renal cell carcinoma (RCC), but adverse events including capillary leak syndrome, potentially mediated through interaction with the high-affinity IL-2R, limit its therapeutic use. Furthermore, antitumor efficacy of IL-2 may also be limited by preferential expansion of immunosuppressive Tregs. ALKS 4230 is an engineered fusion protein comprised of a circularly-permuted IL-2 with the extracellular domain of IL-2Rα, designed to selectively activate effector lymphocytes bearing the intermediate-affinity IL-2R.ALKS 4230 was equipotent to rhIL-2 in activating human cells bearing the intermediate-affinity IL-2R, and less potent than rhIL-2 on cells bearing the high-affinity IL-2R. As observed in vitro with primary human cells from healthy donors and advanced cancer patients, ALKS 4230 induced greater activation and expansion of NK cells with reduced expansion of Tregs relative to rhIL-2. Similarly, in mice, ALKS 4230 treatment stimulated greater expansion of NK cells and memory-phenotype CD8+ T cells at doses that did not expand or activate Tregs. ALKS 4230 treatment induced significantly lower levels of proinflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, and interferon gamma relative to rhIL-2. Furthermore, ALKS 4230 exhibited superior antitumor efficacy in the mouse B16F10 lung tumor model, where ALKS 4230 could be administered via multiple routes of administration and dosing schedules while achieving equivalent antitumor efficacy.ALKS 4230 exhibited enhanced pharmacokinetic and selective pharmacodynamic properties resulting in both improved antitumor efficacy and lower indices of toxicity relative to rhIL-2 in mice. These data highlight the potential of ALKS 4230 as a novel cancer immunotherapy, and as such, the molecule is being evaluated clinically.
Imatinib Long Term Effects (ILTE) Study: An Independent, International Study in CML Patients.
Authors: Carlo Gambacorti-Passerini, Dong-Wook Kim, François-Xavier Mahon, Giuseppe Saglio, Fabrizio Pane, François Guilhot, Michael W.N. Deininger, Arnon Nagler, Alessandro Rambaldi, Enrica Morra, Laura Antolini, IL-Young Kweon, Josy Reiffers, Lucia Tornaghi, Maria Grazia Valsecchi
Journal: Blood (2008)
Effectiveness of the Common Elements Treatment Approach (CETA) in reducing intimate partner violence and hazardous alcohol use in Zambia (VATU): A randomized controlled trial
Authors: Laura K. Murray, Jeremy C. Kane, Nancy Glass, Stephanie Skavenski van Wyk, Flor Melendez, Ravi Paul, Carla Kmett Danielson, Sarah M. Murray, John Mayeya, Francis Simenda, Paul Bolton
Journal: PLoS Medicine (2020)

Both intimate partner violence (IPV) and alcohol misuse are highly prevalent, and partner alcohol misuse is a significant contributor to women's risk for IPV. There are few evidence-based interventions to address these problems in low- and middle-income countries (LMICs). We evaluated the effectiveness of an evidence-based, multi-problem, flexible, transdiagnostic intervention, the Common Elements Treatment Approach (CETA) in reducing (a) women's experience of IPV and (b) their male partner's alcohol misuse among couples in urban Zambia.This was a single-blind, parallel-assignment randomized controlled trial in Lusaka, Zambia. Women who reported moderate or higher levels of IPV and their male partners with hazardous alcohol use were enrolled as a couple and randomized to CETA or treatment as usual plus safety checks (TAU-Plus). The primary outcome, IPV, was assessed by the Severity of Violence Against Women Scale (SVAWS) physical/sexual violence subscale, and the secondary outcome, male alcohol misuse, by the Alcohol Use Disorders Identification Test (AUDIT). Assessors were blinded. Analyses were intent-to-treat. Primary outcome assessments were planned at post-treatment, 12 months post-baseline, and 24 months post-baseline. Enrollment was conducted between May 23, 2016, and December 17, 2016. In total, 123 couples were randomized to CETA, 125 to TAU-Plus. The majority of female (66%) and a plurality of male (48%) participants were between 18 and 35 years of age. Mean reduction in IPV (via SVAWS subscale score) at 12 months post-baseline was statistically significantly greater among women who received CETA compared to women who received TAU-Plus (-8.2, 95% CI -14.9 to -1.5, p = 0.02, Cohen's d effect size = 0.49). Similarly, mean reduction in AUDIT score at 12 months post-baseline was statistically significantly greater among men who received CETA compared to men who received TAU (-4.5, 95% CI -6.9 to -2.2, p < 0.001, Cohen's d effect size = 0.43). The Data and Safety Monitoring Board recommended the trial be stopped early due to treatment effectiveness following the 12-month post-baseline assessment, and CETA was offered to control participants. Limitations of the trial included the lack of a true control condition (i.e., that received no intervention), self-reported outcomes that may be subject to social desirability bias, and low statistical power for secondary IPV outcomes.Results showed that CETA was more effective than TAU-Plus in reducing IPV and hazardous alcohol use among high-risk couples in Zambia. Future research and programming should include tertiary prevention approaches to IPV, such as CETA, rather than offering only community mobilization and primary prevention.The trial was registered on ClinicalTrials.gov (NCT02790827).
British Thoracic Society guideline for the use of long-term macrolides in adults with respiratory disease
Authors: David Smith, Ingrid Du Rand, Charlotte Louise Addy, Timothy Collyns, Simon Paul Hart, Philip J Mitchelmore, Najib M Rahman, Ravijyot Saggu
Journal: Thorax (2020)

Table 1 Summary of outcome measures population intervention Control outcomes Adults with asthma Long-term, lowdose macrolides Placebo ► Quality-of-life measures ► Symptom improvement/symptom score ► Exacerbation rates ► Hospital admission rate ► Disease progression and changes in lung function tests ► Mortality ► Exercise capacity/tolerance ► Sputum volume/colour/character and microbiological resistance/dysbiosis ► Drug monitoring/side effects/toxicity Adults with bronchiectasis Adults with COPD Adults with bronchiolitis obliterans Adults with chronic cough Adults with organising pneumonia Adults with diffuse panbronchiolitisThe use of macrolides as antibacterial agents to treat respiratory infection is excluded.
Clinical Features of Patients with T Cell Large Granular Lymphocyte Leukemia Distinguish Patients with Splenomegaly and Those Who Benefit from Splenectomy.
Authors: Vivek Subbiah, A. Al-kali, M. Wlodarski, Z. Nearman, G. Ramsingh, S. Rosenblatt, A. Lichtin, Jaroslaw P. Maciejewski
Journal: Blood (2006)
Alcoholic drinks and skin cancer - boozing on the beach and beyond (Commentary)
Authors: Jolieke van der Pols
Journal: British Journal of Dermatology (2014)

When the words ‘alcohol’ and ‘skin cancer’ are mentioned together, an image of people consuming alcoholic drinks in a sunny location while exposing themselves to skin cancer- inducing levels of ultraviolet radiation (UVR) readily comes to mind. And there is plenty of evidence to support such an asso- ciation. Alcohol consumption is linked to a variety of risk-tak- ing health behaviours, including getting sunburnt. 1 Thus, from a behavioural point of view, it would seem quite plausi- ble that, on average, frequent drinkers are more often affected by skin cancer than others.
Suicide risk and prevention during the COVID-19 pandemic
Authors: David Gunnell, Louis Appleby, Ella Arensman, Keith Hawton, Ann John, Nav Kapur, Murad Khan, Rory C O'Connor, Jane Pirkis, Louis Appleby, Ella Arensman, Eric D Caine, Lai Fong Chan, Shu-Sen Chang, Ying-Yeh Chen, Helen Christensen, Rakhi Dandona, Michael Eddleston, Annette Erlangsen, David Gunnell, Jill Harkavy-Friedman, Keith Hawton, Ann John, Nav Kapur, Murad Khan, Olivia J Kirtley, Duleeka Knipe, Flemming Konradsen, Shiwei Liu, Sally McManus, Lars Mehlum, Matthew Miller, Paul Moran, Jacqui Morrissey, Christine Moutier, Thomas Niederkrotenthaler, Merete Nordentoft, Rory C O'Connor, Siobhan O'Neill, Andrew Page, Michael R Phillips, Jane Pirkis, Steve Platt, Maurizio Pompili, Ping Qin, Mohsen Rezaeian, Morton Silverman, Mark Sinyor, Steven Stack, Ellen Townsend, Gustavo Turecki, Lakshmi Vijayakumar, Paul SF Yip
Journal: The Lancet Psychiatry (2020)
Lupus antibody-based cancer therapy [Conference Abstract]
Authors: James Hansen, Grace Chan, Yanfeng Liu, Denise Hegan, Shibani Dalal, Eloise Dray, Youngho Kwon, Yuanyuan Xu, Xiaohua Xu, Elizabeth Peterson-Roth, and other
Journal: Cancer Research (2013)

A subset of autoantibodies produced by patients with systemic lupus erythematosus (SLE) penetrates into cell nuclei and binds DNA, and we believe that such antibodies may have applications in cancer therapy. We have discovered that the cell-penetrating, nuclear-localizing anti-DNA lupus antibody 3E10 inhibits key steps in DNA single- and double-strand break repair and has potential for development as a targeted therapy for tumors harboring deficiencies in DNA repair. 3E10 preferentially binds DNA substrates with free single-strand tails and interferes with both base excision repair and homology-directed repair (HDR) in vitro, and HDR efficiency is reduced in cells treated with 3E10 as measured in the chromosome-based DR-GFP fluorescent reporter assay. The binding of 3E10 to DNA can be directly visualized under electron microscopy (EM), and EM studies confirmed that 3E10 interferes with RAD51 filament formation, which is a critical step in HDR. The 3E10 single chain variable fragment penetrates into human tumor xenografts in nude mice, and 3E10 sensitizes cancer cells and tumors to DNA-damaging therapy. In addition, 3E10, by itself, is toxic to BRCA2-deficient cancer cells but not to repair-proficient cells, and when combined with a DNA-damaging agent, 3E10 has a very large cytotoxic effect on BRCA2-deficient cancer cells. The synthetically lethal effect of 3E10 on BRCA2-deficient cancer cells is consistent with our finding that 3E10 inhibits DNA repair, and it suggests that 3E10 has potential as a targeted therapy for tumors harboring deficiencies in DNA repair, such as certain breast, ovarian, and prostate cancers. Of note, patients with SLE have lower than expected incidence rates of breast, ovarian, and prostate cancers, and it is tempting to speculate that the circulating cell-penetrating anti-DNA autoantibodies provide patients with SLE some protection against the development of DNA repair-deficient tumors. In summary, our work with the 3E10 antibody has provided proof of principle for the development of a lupus antibody as a cancer therapy and opened up new avenues for exploration into the biology of lupus antibodies.
Single-cell RNA-sequencing reveals profound changes in circulating immune cells in patients with heart failure
Authors: Wesley T Abplanalp, David John, Sebastian Cremer, Birgit Assmus, Lena Dorsheimer, Jedrzej Hoffmann, Graziella Becker-Pergola, Michael A Rieger, Andreas M Zeiher, Mariuca Vasa-Nicotera, Stefanie Dimmeler
Journal: Cardiovascular Research (2020)

Identification of signatures of immune cells at single-cell level may provide novel insights into changes of immune-related disorders. Therefore, we used single-cell RNA-sequencing to determine the impact of heart failure on circulating immune cells.We demonstrate a significant change in monocyte to T-cell ratio in patients with heart failure, compared to healthy subjects, which were validated by flow cytometry analysis. Subclustering of monocytes and stratification of the clusters according to relative CD14 and FCGR3A (CD16) expression allowed annotation of classical, intermediate, and non-classical monocytes. Heart failure had a specific impact on the gene expression patterns in these subpopulations. Metabolically active genes such as FABP5 were highly enriched in classical monocytes of heart failure patients, whereas β-catenin expression was significantly higher in intermediate monocytes. The selective regulation of signatures in the monocyte subpopulations was validated by classical and multifactor dimensionality reduction flow cytometry analyses.Together this study shows that circulating cells derived from patients with heart failure have altered phenotypes. These data provide a rich source for identification of signatures of immune cells in heart failure compared to healthy subjects. The observed increase in FABP5 and signatures of Wnt signalling may contribute to enhanced monocyte activation.
The effect of air pollutants on airway innate immune cells in patients with asthma
Authors: Jihyun Kim, Young‐Chan Kim, Jongho Ham, Kyoung‐Hee Sohn, Suh‐Young Lee, Doo Hyun Chung, Sang‐Heon Cho, Hye Ryun Kang, Hye Young Kim
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Dietary Therapies Induce Rapid Response and Remission in Pediatric Patients With Active Crohn’s Disease
Authors: Rotem Sigall Boneh, Johan Van Limbergen, Eytan Wine, Amit Assa, Ron Shaoul, Peri Milman, Shlomi Cohen, Michal Kori, Sarit Peleg, Avi On, Hussein Shamaly, Lee Abramas, Arie Levine
Journal: Clinical Gastroenterology and Hepatology (2020)
Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity
Authors: Jarle Bruun, Kushtrim Kryeziu, Peter W. Eide, Seyed H. Moosavi, Ina A. Eilertsen, Jonas Langerud, Bård Røsok, Max Z. Totland, Tuva H. Brunsell, Teijo Pellinen, Jani Saarela, Christian H. Bergsland, Hector G. Palmer, Kristoffer W. Brudvik, Tormod Guren, Rodrigo Dienstmann, Marianne G. Guren, Arild Nesbakken, Bjørn Atle Bjørnbeth, Anita Sveen, Ragnhild A. Lothe
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer. Experimental Design: We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients. Results: Three drug–response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2–5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS-mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression. Conclusions: Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression–based predictive signatures to guide experimental therapies.
Association between alcohol use and violence-related injury in emergency department patients in Moshi, Tanzania: analysis of a prospective trauma registry
Authors: Kaitlyn Friedman, Julius Raymond, Mary Catherine Minnig, Francis Sakita, Joao Ricardo Nickenig Vissoci, Catherine Staton
Journal: The Lancet Global Health (2020)

BackgroundHarmful and hazardous alcohol use and violence are major contributors to global mortality and morbidity, despite being both predictable and preventable. This study seeks to quantify the association between violence-related injury and alcohol use disorders in a referral hospital in Moshi, Tanzania using a prospective trauma registry.MethodsWe included all adult trauma patients (>17 years of age) presenting to the Kilimanjaro Christian Medical Center in Moshi, Tanzania in the registry. The trauma registry is an extensive instrument that was translated and back-translated from English to Kiswahili by local research assistants. The registry includes demographic information, patient history, clinical diagnosis and treatment, injury and surgery information, the Patient Health Questionnaire-2 (PHQ2), a behavioural health assessment, the Alcohol Use Disorders Identification Test (AUDIT), and substance use screening. An AUDIT score of ≥8 indicates harmful alcohol use in this setting. Alcohol use in the 6 h prior before injury was determined either from self-report or a blood alcohol concentration above 0. Category of injury (violence or non-violence) was self-reported.FindingsWe included data from 500 patients enrolled in the trauma registry between April 17, 2018, and Jan 12, 2019. Of these, 84 patients (16·8%) reported that their injury was due to violence. Patients with violence-related injuries were 2·21 times more likely to have a positive alcohol status than were patients who presented with injuries not related to violence (95% CI 1·36–3·60; p<0·01). Among patients with violence-related injuries, those with a positive alcohol status were 6·26 times more likely to have an AUDIT score ≥8 than were patients with a negative alcohol status (95% CI 2·13–18·39; p<0·001).InterpretationAlcohol use and violence-related injury pose a significant threat to health and wellbeing globally. In Moshi, Tanzania, both issues are prevalent and contribute to the burden of injury. To adequately reduce violence-related injuries in this setting, it is necessary to address harmful alcohol use.FundingFogarty International Center of the National Institutes of Health under Award Number K01TW010000 (PI, Staton) and the Duke Global Health Institute.
Use of Frozen Embryo Transfer During Fertility Treatment and Risk of Childhood Cancer
Authors: Lodovico Parmegiani, Gábor Vajta
Journal: JAMA (2020)

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Continuous mitotic activity of primitive hematopoietic stem cells in adult mice
Authors: Mina N.F. Morcos, Thomas Zerjatke, Ingmar Glauche, Clara M. Munz, Yan Ge, Andreas Petzold, Susanne Reinhardt, Andreas Dahl, Natasha S. Anstee, Ruzhica Bogeska, Michael D. Milsom, Petter Säwén, Haixia Wan, David Bryder, Axel Roers, Alexander Gerbaulet
Journal: The Journal of Experimental Medicine (2020)

The proliferative activity of aging hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that primitive HSCs symmetrically divide only four times to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in HSCs with high repopulation potential. We argue that this background had been misinterpreted as stable retention of induced label. We found cell division–independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support abrupt entry of HSCs into permanent quiescence or sudden loss of regeneration potential after four divisions, but show that primitive HSCs of adult mice continue to cycle rarely.
Incidence of Catheter-Associated Urinary Tract Infections With Compliance With Preventive Guidelines
Authors: SreyRam Kuy, Rohit Gupta, Cayla Roy, Samir Awad
Journal: JAMA Surgery (2020)

This study describes the incidence of catheter-associated urinary tract infections in a large academic medical center and shows that even with prevention guideline adherence, catheter-associated urinary tract infections cannot truly be a never event.