tbuckley/cabot-search huggingface dataset:
RBMS1 Suppresses Colon Cancer Metastasis through Targeted Stabilization of Its mRNA Regulon
Authors: Johnny Yu, Albertas Navickas, Hosseinali Asgharian, Bruce Culbertson, Lisa Fish, Kristle Garcia, John Paolo Olegario, Maria Dermit, Martin Dodel, Benjamin Hänisch, Yikai Luo, Ethan M. Weinberg, Rodrigo Dienstmann, Robert S. Warren, Faraz K. Mardakheh, Hani Goodarzi
Journal: Cancer Discovery (2020)

Identifying master regulators that drive pathologic gene expression is a key challenge in precision oncology. Here, we have developed an analytic framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a posttranscriptional regulator of RNA stability by directly binding its target mRNAs. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients. SIGNIFICANCE: By applying a new analytic approach to transcriptomic data from clinical samples and models of colon cancer progression, we have identified RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival.See related commentary by Carter, p. 1261.This article is highlighted in the In This Issue feature, p. 1241.
The EMT Transcription Factor ZEB2 Promotes Proliferation of Primary and Metastatic Melanoma While Suppressing an Invasive, Mesenchymal-Like Phenotype
Authors: Niels Vandamme, Geertrui Denecker, Kenneth Bruneel, Gillian Blancke, Özden Akay, Joachim Taminau, Jordy De Coninck, Eva De Smedt, Nicolas Skrypek, Wouter Van Loocke, Jasper Wouters, David Nittner, Corinna Köhler, Douglas S. Darling, Phil F. Cheng, Marieke I.G. Raaijmakers, Mitchell P. Levesque, Udupi Girish Mallya, Mairin Rafferty, Balazs Balint, William M. Gallagher, Lieve Brochez, Danny Huylebroeck, Jody J. Haigh, Vanessa Andries, Florian Rambow, Pieter Van Vlierberghe, Steven Goossens, Joost J. van den Oord, Jean-Christophe Marine, Geert Berx
Journal: Cancer Research (2020)

Abstract Epithelial-to-mesenchymal transition (EMT)-inducing transcription factors (TF) are well known for their ability to induce mesenchymal states associated with increased migratory and invasive properties. Unexpectedly, nuclear expression of the EMT-TF ZEB2 in human primary melanoma has been shown to correlate with reduced invasion. We report here that ZEB2 is required for outgrowth for primary melanomas and metastases at secondary sites. Ablation of Zeb2 hampered outgrowth of primary melanomas in vivo, whereas ectopic expression enhanced proliferation and growth at both primary and secondary sites. Gain of Zeb2 expression in pulmonary-residing melanoma cells promoted the development of macroscopic lesions. In vivo fate mapping made clear that melanoma cells undergo a conversion in state where ZEB2 expression is replaced by ZEB1 expression associated with gain of an invasive phenotype. These findings suggest that reversible switching of the ZEB2/ZEB1 ratio enhances melanoma metastatic dissemination. Significance: ZEB2 function exerts opposing behaviors in melanoma by promoting proliferation and expansion and conversely inhibiting invasiveness, which could be of future clinical relevance.
Intermittent Vs Continuous Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study
Authors: Birgitte Klug Albertsen, Jonas Abrahamsson, Bendik Lund, Kim Vettenranta, Ólafur G. Jónsson, Thomas Leth Frandsen, Benjamin Ole Wolthers, Kathrine Grell, Mats Heyman, Kjeld Schmiegelow
Journal: Blood (2017)
Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders
Authors: Jatin Machhi, Bhavesh D. Kevadiya, Ijaz Khan Muhammad, Jonathan Herskovitz, Katherine E. Olson, R. Lee Mosley, Howard E. Gendelman
Journal: Molecular Neurodegeneration (2020)

Emerging evidence demonstrates that adaptive immunity influences the pathobiology of neurodegenerative disorders. Misfolded aggregated self-proteins can break immune tolerance leading to the induction of autoreactive effector T cells (Teffs) with associated decreases in anti-inflammatory neuroprotective regulatory T cells (Tregs). An imbalance between Teffs and Tregs leads to microglial activation, inflammation and neuronal injury. The cascade of such a disordered immunity includes the drainage of the aggregated protein antigens into cervical lymph nodes serving to amplify effector immune responses. Both preclinical and clinical studies demonstrate transformation of this altered immunity for therapeutic gain. We posit that the signs and symptoms of common neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke can be attenuated by boosting Treg activities.
A systematic review evaluating the implementation of technologies to assess, monitor and treat neurodevelopmental disorders: A map of the current evidence
Authors: Althea Z. Valentine, Beverley J. Brown, Madeleine J. Groom, Emma Young, Chris Hollis, Charlotte L. Hall
Journal: Clinical Psychology Review (2020)

Technology-based interventions provide an attractive option for improving service provision for neurodevelopmental disorders (NDD), for example, widening access to interventions, objective assessment, and monitoring; however, it is unclear whether there is sufficient evidence to support their use in clinical settings. This review provides an evidence map describing how technology is implemented in the assessment/diagnosis and monitoring/ treatment of NDD (Prospero CRD42018091156). Using predefined search terms in six databases, 7982 articles were identified, 808 full-texts were screened, resulting in 47 included papers. These studies were appraised and synthesised according to the following outcomes of interest: effectiveness (clinical effectiveness/ service delivery efficiencies), economic impact, and user impact (acceptability/ feasibility). The findings describe how technology is currently being utilised clinically, highlights gaps in knowledge, and discusses future research needs. Technology has been used to facilitate assessment and treatment across multiple NDD, especially Autism Spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders. Technologies include mobile apps/tablets, robots, gaming, computerised tests, videos, and virtual reality. The outcomes presented largely focus on the clinical effectiveness of the technology, with approximately half the papers demonstrating some degree of effectiveness, however, the methodological quality of many studies is limited. Further research should focus on randomised controlled trial designs with longer follow-up periods, incorporating an economic evaluation, as well as qualitative studies including process evaluations and user impact.
Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers
Authors: Soo-Chin Lee, Noriko Shimasaki, Joline S.J. Lim, Andrea Wong, Kritika Yadav, Wei Peng Yong, Lip Kun Tan, Liang Piu Koh, Michelle L.M. Poon, Sing Huang Tan, Samuel G.W. Ow, Lavina Bharwani, Yoon Sim Yap, Mabel Z.Q. Foo, Elaine Coustan-Smith, Raghav Sundar, Hon Lyn Tan, Wan Qin Chong, Nesaretnam Barr Kumarakulasinghe, Jedidah L.M. Lieow, Priscillia J.X. Koe, Boon Cher Goh, Dario Campana
Journal: Clinical Cancer Research (2020)

Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies.In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy.In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment.NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.
Abstract A32: Clinical significance of liquid biopsy in glioblastoma patients through tissue analysis
Authors: Rashmi Rana, Rajesh Acharya, Satnam Singh Chhabra, Sunila Jain
Journal: Clinical Cancer Research (2020)

Abstract Glioblastoma multiforme is the most fatal form of brain tumor, distinguished as an aggressive growth and assists annexing by cell relocation and mortification of extracellular matrix with average survival rate of approximately 6-14 months. The majority of patients suffer recurrence due to molecular heterogeneity of glioblastoma and deregulation of many signaling pathways involved in proliferation, survival, and apoptosis. However, genetic profiling of the tumor is shown to classify disease and therapy response. Although brain surgery is involved for tissue collection, repeated tumor biopsies may be necessary for accurate genotyping over the course of the disease. While the detection of circulating tumor DNA (ctDNA) in the blood of patients with primary brain tumors remains challenging, sequencing of ctDNA from the tissue may provide an alternative way to glioblastoma genotype with morbidity and lower cost. We therefore evaluated the depiction of the glioblastoma genome in tissue from 40 patients with glioblastoma. Here we demonstrated that tumor-derived DNA was detected in tissue from 40 patients and was associated with disease load and adverse effect. The genomic landscape of glioblastoma in the tissue included a broad spectrum of genetic alterations and directly resembled the genomes of tumor biopsies. Alterations that were found during tumorigenesis and mutations in the metabolic pathway gene isocitrate dehydrogenase (IDH1, IDH2) were shared in all matched ctDNA-positive tissue-tumor pairs, whereas growth factor receptor signaling pathways showed significant progress. The ability to monitor the evolution of the glioblastoma genome through an invasive technique could advance the clinical application and use of genotype-directed therapies for glioblastoma, one of the most aggressive human cancers. Citation Format: Rashmi Rana, Rajesh Acharya, Satnam Singh Chhabra, Sunila Jain. Clinical significance of liquid biopsy in glioblastoma patients through tissue analysis [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A32.
COVID-19 pandemic: an opportunity to assess the utility of telemedicine in patients with rheumatic diseases
Authors: Clementina López-Medina, Alejandro Escudero, Eduardo Collantes-Estevez
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the letter published by Bozzalla Cassione et al ,1 in which authors evaluated 165 patients with systemic lupus erythematosus using telemedicine as the follow-up method. As in Italy, the high infectivity and the risk of collapse of intensive care units led to the Spanish government to announce on 14 March the strict confinement and prohibition of social mobility to ensure a decrease in COVID-19 contagion rates. As a consequence, physical consultations of rheumatology outpatients have been replaced by phone consultations to prevent the risk of contagion.2 One of the most important concerns that limits the care quality of rheumatic patients in Spain is the pressure of healthcare, since the number of patients is excessive and human resources are limited. This epidemic outbreak has proven to be a great opportunity to test phone consultations in assisting rheumatic patients. The rheumatology department of Reina Sofia University Hospital in Cordoba (Spain) conducted a survey among rheumatic patients that was disseminated via patient …
THU0442 GOUT AND HEART FAILURE IN THE US: A NATIONAL PERSPECTIVE
Authors: G. Singh, M. Sehgal, A. Mithal
Journal: Annals of the Rheumatic Diseases (2020)

Background: Heart failure (HF) is the eighth leading cause of death in the US, with a 38% increase in the number of deaths due to HF from 2011 to 2017 (1). Gout and hyperuricemia have previously been recognized as significant risk factors for heart failure (2), but there is little nationwide data on the clinical and economic consequences of these comorbidities. Objectives: To study heart failure hospitalizations in patients with gout in the United States (US) and estimate their clinical and economic impact. Methods: The Nationwide Inpatient Sample (NIS) is a stratified random sample of all US community hospitals. It is the only US national hospital database with information on all patients, regardless of payer, including persons covered by Medicare, Medicaid, private insurance, and the uninsured. We examined all inpatient hospitalizations in the NIS in 2017, the most recent year of available data, with a primary or secondary diagnosis of gout and heart failure. Over 69,800 ICD 10 diagnoses were collapsed into a smaller number of clinically meaningful categories, consistent with the CDC Clinical Classification Software. Results: There were 35.8 million all-cause hospitalizations in patients in the US in 2017. Of these, 351,735 hospitalizations occurred for acute and/or chronic heart failure in patients with gout. These patients had a mean age of 73.3 years (95% confidence intervals 73.1 – 73.5 years) and were more likely to be male (63.4%). The average length of hospitalization was 6.1 days (95% confidence intervals 6.0 to 6.2 days) with a case fatality rate of 3.5% (95% confidence intervals 3.4% – 3.7%). The average cost of each hospitalization was $63,992 (95% confidence intervals $61,908 - $66,075), with a total annual national cost estimate of $22.8 billion (95% confidence intervals $21.7 billion - $24.0 billion). Conclusion: While gout and hyperuricemia have long been recognized as potential risk factors for heart failure, the aging of the US population is projected to significantly increase the burden of illness and costs of care of these comorbidities (1). This calls for an increased awareness and management of serious co-morbid conditions in patients with gout. References: [1]Sidney, S., Go, A. S., Jaffe, M. G., Solomon, M. D., Ambrosy, A. P., &amp; Rana, J. S. (2019). Association Between Aging of the US Population and Heart Disease Mortality From 2011 to 2017. JAMA Cardiology. doi:10.1001/jamacardio.2019.4187 [2]Krishnan E. Gout and the risk for incident heart failure and systolic dysfunction. BMJ Open 2012;2:e000282.doi:10.1136/bmjopen-2011-000282 Disclosure of Interests: : Gurkirpal Singh Grant/research support from: Horizon Therapeutics, Maanek Sehgal: None declared, Alka Mithal: None declared
The pediatric precision oncology study INFORM: Clinical outcome and benefit for molecular subgroups.
Authors: Cornelis Martinus van Tilburg, Elke Pfaff, Kristian W. Pajtler, Karin P.S. Langenberg, Petra Fiesel, Barbara C. Jones, Gnana Prakash Balasubramanian, Sebastian Stark, Pascal D. Johann, Mirjam Blattner-Johnson, Kathrin Schramm, Natalie Jäger, Andreas von Deimling, Uta Dirksen, Angelika Freitag, Ruth Witt, Peter Lichter, David T.W. Jones, Stefan M. Pfister, Olaf Witt
Journal: Journal of Clinical Oncology (2020)

LBA10503 Background: Several pediatric precision oncology programs have identified molecular actionable variants. However, the clinical benefit is largely unknown. We here report a target prioritization algorithm and associated clinical outcome. Methods: INFORM is a prospective, non-interventional, multi-center, multi-national, and feasibility registry collecting clinical and molecular data. Patients with refractory/relapsed/progressive malignant disease, including primary diagnosis high-risk entities, can be enrolled. Fresh frozen tumor material (incl. germline DNA) was subjected to WES, lcWGS, RNA-Seq, RNA expression array and DNA-methylation. A weekly interdisciplinary molecular board reviewed and prioritized alterations based on a 7- step scale from ‘very high’ to ‘very low’, depending on the type of alteration and its entity specific relevance (described by Worst et al. Eur J Cancer 2016). Results: To date, more than 1300 patients were enrolled. 525 patients finished follow-up and were included in this analysis. They were enrolled in 72 centers in 8 countries. The median age was 12.0 (range 0 - 40) years. Average turnaround time from submission to report was 25.4 days. Median PFS and OS were 116 (95% CI 105 – 135) and 289 (95% CI 250 – 335) days. The distribution of the highest priority target per patient was: very high 8.0%, high 14.8%, moderate 20.3%, intermediate 23.6%, borderline 14.4%, low 2.5%, very low 1.0% and no actionable target 15.4%. 149 patients received targeted treatment on the basis of identified targets, of which 20 had a very high priority target (mostly ALK, BRAF and NRAS mutations and MET and NTRK-fusions) with a median PFS of 204.5 (95% CI 91.0 – 628.0) compared to 114 (95% CI 103 – 133) days in all other 505 patients (p = 0.0095). OS did not show clinically relevant differences. Explorative analysis of the time to progression (TTP) ratio (before compared to after enrollment) showed that patients treated according to a very high priority target had a higher TTP ratio (1.0) compared to all other patients (0.7). Possible predisposition syndromes were identified in 7.8% of patients, half of which were newly diagnosed. Methylation analysis provided a diagnosis refinement in 8% of CNS tumors. Conclusions: Pediatric precision oncology in a real world, multi-national setting is feasible. The prioritization algorithm identifies subgroups benefitting from molecularly matched targeted treatment. Still, for the patients without a very high priority target further layers of molecular and functional data should be incorporated in future programs.
Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials
Authors: Chloe Orkin, Edwin DeJesus, Paul E Sax, Jose R Arribas, Samir K Gupta, Claudia Martorell, Jeffrey L Stephens, Hans-Jurgen Stellbrink, David Wohl, Franco Maggiolo, Melanie A Thompson, Daniel Podzamczer, Debbie Hagins, Jason A Flamm, Cynthia Brinson, Amanda Clarke, Hailin Huang, Rima Acosta, Diana M Brainard, Sean E Collins, Hal Martin
Journal: The Lancet HIV (2020)
THU0649-HPR ASSESSMENT OF THE EFFECTIVENESS OF THE EDUCATIONAL PROGRAM FOR PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: M. Salokhiddinov, F. Umarov
Journal: Annals of the Rheumatic Diseases (2020)

Background: Effective therapy of rheumatoid arthritis (RA) is impossible without the active and competent participation of the patient in this process, which requires educational programs based on the real needs of the patient Objectives: The purpose of the study was to develop an educational program for patients with RA and evaluate its effectiveness Methods: The study included 65 patients with RA. 35 patients of the main group were trained in the educational program. Of these, 30 patients made up the control group. The educational program consisted of 4 daily classes of 90 minutes. Initially and after 6 months, the indices DAS28, HAQ, RAPID3 were determined using the MDHAQ questionnaire Results: After 6 months after training in the main group, the DAS28 index decreased by 1.28 ± 0.28 points (p &lt;0.05), HAQ - by 0.65 ± 0.39 (55.2%) (p &lt;0.01), RAPID3 - by 4.87 ± 0.82 (45.6%) (p &lt;0.01), anxiety level - by 0.78 ± 0.28 (52.1%) (p &lt; 0.05), depression - by 0.76 ± 0.54 (43.4%) (p &lt;0.05), fatigue - by 2.96 ± 1.21 points (42.3%) (p &lt;0, 05), sleep improved by 0.85 ± 0.34 (52.3%) (p &lt;0.05). 6 months after participating in the educational program, a good response to treatment according to DAS28 according to EULAR criteria was significantly more often recorded (54.5% versus 29.0% in the control group (p &lt;0.05), and the number of patients noted improvement well-being increased by 9 times (p &lt;0.01). The dynamics in the control group was less pronounced, which determined statistically significant differences between groups for most indicators (p &lt;0.05) Conclusion: The educational program improves functional capabilities, psychological status, helps control the activity of the disease and improves the quality of life of patients with RA References: [1]Chen SY Wang. The Relationship between Physical Function, Knowledge of Disease, Social Support and Self care behavior in Patients with Rheumatoid Arthritis. Journal of Nursing Research. 2007;15:183–191. [2]Taal E, Rasker JJ, Seydel ER, Wiegman O. Health Status, adherence with health recommendations, self-efficacy and social support in patients with rheumatoid arthritis. Patient Education &amp; Counseling. 1993;20:63–76. Acknowledgments: I would like to thank to all my Prof Ahmedov and department of Rheumatology for their sincere support Disclosure of Interests: None declared