tbuckley/cabot-search huggingface dataset:
Being Affable, Available, and Able Is Not Enough
Authors: Muneera R. Kapadia, Kathleen Kieran
Journal: JAMA Surgery (2020)

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Targeting the SAGA and ATAC Transcriptional Coactivator Complexes in MYC-Driven Cancers
Authors: Lisa Maria Mustachio, Jason Roszik, Aimee Farria, Sharon Y.R. Dent
Journal: Cancer Research (2020)

Abstract Targeting epigenetic regulators, such as histone-modifying enzymes, provides novel strategies for cancer therapy. The GCN5 lysine acetyltransferase (KAT) functions together with MYC both during normal development and in oncogenesis. As transcription factors, MYC family members are difficult to target with small-molecule inhibitors, but the acetyltransferase domain and the bromodomain in GCN5 might provide alternative targets for disruption of MYC-driven functions. GCN5 is part of two distinct multiprotein histone-modifying complexes, SAGA and ATAC. This review summarizes key findings on the roles of SAGA and ATAC in embryo development and in cancer to better understand the functional relationships of these complexes with MYC family members, as well as their future potential as therapeutic targets.
Differential Type 2 cytokine responses and group 2 innate lymphoid cell (ILC2) activation among 44 strains of mice in the Collaborative Cross following Alternaria extract challenge
Authors: Marc Todd, Liddy Malone, Mark Rusznak, Matthew Stier, Jian Zhang, Kasia Goleniewska, Weisong Zhou, Stokes Peebles, Shinji Toki
Journal: Journal of Allergy and Clinical Immunology (2020)
Nutritional status in tricuspid regurgitation: implications of transcatheter repair
Authors: Christian Besler, Matthias Unterhuber, Karl‐Philipp Rommel, Elisabeth Unger, Philipp Hartung, Maximilian von Roeder, Thilo Noack, Markus Zachäus, Ulrich Halm, Michael Borger, Steffen Desch, Holger Thiele, Philipp Lurz
Journal: European Journal of Heart Failure (2020)

Abstract Aims To characterize the prevalence and clinical relevance of malnutrition in patients undergoing transcatheter tricuspid valve edge‐to‐edge repair (TTVR). Methods and results Overall, 86 consecutive patients (mean age 78 ± 7 years) with moderate‐to‐severe tricuspid regurgitation (TR) at prohibitive surgical risk were analysed. Mini Nutritional Assessment (MNA), quality of life assessment, 6‐min walk test distance and laboratory analyses were performed before and 1 month after TTVR. A total of 43 patients (50%) underwent concomitant transcatheter mitral valve repair. According to MNA, 81 patients (94%) were malnourished or at risk of malnutrition before TTVR. Following TTVR, MNA improved in 64 patients (74%). As compared to patients without MNA improvement, patients with increased MNA score had greater reductions in TR [regurgitation volume −17.0 (interquartile range, IQR −25.0; −7.0) mL vs. −26.4 (IQR −40.3; −14.5) mL, P &lt; 0.001] and inferior vena cava diameter. Only patients with increased MNA score displayed a decrease in N‐terminal pro‐brain natriuretic peptide levels [−320 (IQR −1294; 105) pg/mL vs. +708 (IQR −342; 2708) pg/mL, P = 0.009], improvements in cholinesterase levels (0.0 ± 11.9 μmoL/L vs. +10.9 ± 16.7 μmoL/L, P &lt; 0.001) and renal function during follow‐up. Beneficial effects on quality of life scores and 6‐min walk test distance following TTVR were observed exclusively in patients with improvement in MNA. During a median follow‐up of 6 months, patients with worsened MNA had an increased risk of death and rehospitalization for heart failure. Conclusion Nutritional impairment is common and of prognostic importance in patients undergoing TTVR. Hepatorenal function modestly improves after successful TTVR. Further study of extracardiac implications of TR‐associated right heart failure is warranted to improve care in this vulnerable patient population.
Prognostic value of risk stratification using blood biochemical parameters in Japanese patients with metastatic renal cell carcinoma treated by nivolumab.
Authors: Yoshiaki Yamamoto, Hideyasu Matsuyama, Hiroaki Matsumoto, Shigeru Sakano, Nakanori Fujii, Kazuo Oba, Mitsutaka Yamamoto, Yoriaki Kamiryo, Takeshi Hiragino, Kazuhiro Nagao, Kimio Takai, Akihiko Aoki, Satoru Yoshihiro, Manabu Tsukamoto, Jumpei Akao, Seiji Kitahara, Taku Misumi, Hirotaka Komatsu, Shintaro Oka, Akinobu Suga
Journal: Journal of Clinical Oncology (2020)

724 Background: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma (RCC). However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic RCC. Methods: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic RCC and who received nivolumab. MSKCC and IMDC risk, inflammation-based prognostic scores, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific and overall survival were compared using Cox proportional-hazards regression models. Results: Univariate analysis showed that MSKCC risk score ( P = 0.0052), lactate dehydrogenase (LDH) ( P = 0.0266), LMR ( P = 0.0113), and PLR ( P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that PLR and LDH were found to be independent prognostic factors for disease-specific survival ( P = 0.0008, RR = 7.95, 95% CI, 2.16–51.64 and P = 0.0123, RR = 3.92, 95% CI, 1.37–10.80, respectively). The combination of PLR and LDH was the most significant prognostic biomarker in metastatic RCC for disease-specific ( P &lt; 0.0001) and overall ( P &lt; 0.0001) survival. Changes in LMR and PLR in response to nivolumab were significant prognostic factors for disease-specific survival ( P &lt; 0.0001 and P = 0.0477, respectively). Conclusions: The combination of PLR and LDH may be a potential biomarker for estimating disease-specific and overall survival in Japanese patients with metastatic RCC treated by nivolumab. If changes of inflammation-based prognostic scores in response to nivolumab treatment might be improved, nivolumab treatment should be continued.
Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth
Authors: Michelle A. Francisco, Siyi Wanggou, Jerry J. Fan, Weifan Dong, Xin Chen, Ali Momin, Namal Abeysundara, Hyun-Kee Min, Jade Chan, Rochelle McAdam, Marian Sia, Ronwell J. Pusong, Shixuan Liu, Nish Patel, Vijay Ramaswamy, Noriyuki Kijima, Lu-Yang Wang, Yuanquan Song, Ran Kafri, Michael D. Taylor, Xuejun Li, Xi Huang
Journal: The Journal of Experimental Medicine (2020)

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.
Transcriptome-wide and differential expression network analyses of childhood asthma in nasal epithelium
Authors: Erick Forno, Rong Zhang, Yale Jiang, Soyeon Kim, Qi Yan, Zhao Ren, Yueh-Ying Han, Nadia Boutaoui, Franziska Rosser, Daniel E. Weeks, Edna Acosta-Pérez, Angel Colón-Semidey, María Alvarez, Glorisa Canino, Wei Chen, Juan C. Celedón
Journal: Journal of Allergy and Clinical Immunology (2020)
Berberine-containing Natural Medicine Confers Sustained Peanut Tolerance Associated with Distinct Microbiota Signature
Authors: Kamal Srivastava, Ozkan Fidan, YianMei Shi, Nan Yang, Changda Liu, Ying Song, Anna Nowak-Wegrzyn, Nasreen Haque, Jixun Zhan, Xiu-Min Li
Journal: Journal of Allergy and Clinical Immunology (2020)
A novel digital intervention for actively reducing severity of paediatric ADHD (STARS-ADHD): a randomised controlled trial
Authors: Scott H Kollins, Denton J DeLoss, Elena Cañadas, Jacqueline Lutz, Robert L Findling, Richard S E Keefe, Jeffery N Epstein, Andrew J Cutler, Stephen V Faraone
Journal: The Lancet Digital Health (2020)

Attention-deficit hyperactivity disorder (ADHD) is a common paediatric neurodevelopmental disorder with substantial effect on families and society. Alternatives to traditional care, including novel digital therapeutics, have shown promise to remediate cognitive deficits associated with this disorder and may address barriers to standard therapies, such as pharmacological interventions and behavioural therapy. AKL-T01 is an investigational digital therapeutic designed to target attention and cognitive control delivered through a video game-like interface via at-home play for 25 min per day, 5 days per week for 4 weeks. This study aimed to assess whether AKL-T01 improved attentional performance in paediatric patients with ADHD.The Software Treatment for Actively Reducing Severity of ADHD (STARS-ADHD) was a randomised, double-blind, parallel-group, controlled trial of paediatric patients (aged 8-12 years, without disorder-related medications) with confirmed ADHD and Test of Variables of Attention (TOVA) Attention Performance Index (API) scores of -1·8 and below done by 20 research institutions in the USA. Patients were randomly assigned 1:1 to AKL-T01 or a digital control intervention. The primary outcome was mean change in TOVA API from pre-intervention to post-intervention. Safety, tolerability, and compliance were also assessed. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02674633 and is completed.Between July 15, 2016, and Nov 30, 2017, 857 patients were evaluated and 348 were randomly assigned to receive AKL-T01 or control. Among patients who received AKL-T01 (n=180 [52%]; mean [SD] age, 9·7 [1·3] years) or control (n=168 [48%]; mean [SD] age, 9·6 [1·3] years), the non-parametric estimate of the population median change from baseline TOVA API was 0·88 (95% CI 0·24-1·49; p=0·0060). The mean (SD) change from baseline on the TOVA API was 0·93 (3·15) in the AKL-T01 group and 0·03 (3·16) in the control group. There were no serious adverse events or discontinuations. Treatment-related adverse events were mild and included frustration (5 [3%] of 180) and headache (3 [2%] of 180). Patient compliance was a mean of 83 (83%) of 100 expected sessions played (SD, 29·2 sessions).Although future research is needed for this digital intervention, this study provides evidence that AKL-T01 might be used to improve objectively measured inattention in paediatric patients with ADHD, while presenting minimal adverse events.Sponsored by Akili Interactive Labs.
Stress and Psychiatric Disorders: The Role of Mitochondria
Authors: Teresa E. Daniels, Elizabeth M. Olsen, Audrey R. Tyrka
Journal: Annual Review of Clinical Psychology (2020)

In seeking to understand mental health and disease, it is fundamental to identify the biological substrates that draw together the experiences and physiological processes that underlie observed psychological changes. Mitochondria are subcellular organelles best known for their central role in energetics, producing adenosine triphosphate to power most cellular processes. Converging lines of evidence indicate that mitochondria play a key role in the biological embedding of adversity. Preclinical research documents the effects of stress exposure on mitochondrial structure and function, and recent human research suggests alterations constituting recalibrations, both adaptive and nonadaptive. Current research suggests dynamic relationships among stress exposure, neuroendocrine signaling, inflammation, and mitochondrial function. These complex relationships are implicated in disease risk, and their elucidation may inform prevention and treatment of stress- and trauma-related disorders. We review and evaluate the evidence for mitochondrial dysfunction as a consequence of stress exposure and as a contributing factor to psychiatric disease.
Hyperthermia and smart drug delivery systems for solid tumor therapy
Authors: A.L.B. Seynhaeve, M. Amin, D. Haemmerich, G.C. van Rhoon, T.L.M. ten Hagen
Journal: Advanced Drug Delivery Reviews (2020)

Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery.
Safety and efficacy of tivozanib in first-line metastatic renal cell carcinoma: A multicenter compassionate use study.
Authors: Umberto Basso, Giuseppe Procopio, Giuseppe Fornarini, Francesco Massari, Alessandra Bearz, Lucia Fratino, Michele Milella, Maria Bassanelli, Cosimo Sacco, Davide Bimbatti, Elena Verzoni, Mimma Rizzo, Camillo Porta
Journal: Journal of Clinical Oncology (2020)

632 Background: Tivozanib-TIVO is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR-2, and VEGFR-3. TIVO was recently approved in Europe for the first line treatment of metastatic Renal Cell Carcinoma-RCC after a randomized trial demonstrated improved PFS and different safety profile compared to sorafenib. Methods: Retrospective analysis of safety and activity of TIVO administered within a compassionate use program to pts with metastatic RCC with no prior systemic treatment. Results: From Aug 2018 to Apr 2019, 64 pts have started TIVO at 1,34 mg daily (three weeks on, 1 week off) in 9 Italian Oncology Units. Median age was 67.5 years (range 40 to 85), 61% males, median creatinine clearance 63 ml/min(range 30-97). According to IDMC criteria, 27.5 % of pts were good prognosis, 60% intermediate and 10.5 % poor. Primary tumor had been removed in 70.5% of pts. Histology was clear cell 89.5%, papillary 4.5%, unclassified 6%. Response rate was 46.5%, stable disease 37.5%, progression 16%. Grade 3-4 toxicities were 4.5% hypertension, 3% mucositis, 1.5% diarrhea and 1.5% anorexia. Dose reduction to 0.89 mg was applied to 15.5% of pts. PFS and OS data will be presented at the Meeting. Conclusions: TIVO showed good activity and favorable safety profile in a real world cohort of unselected pts with metastatic RCC. Predictive biomarkers of response to antiangiogenic therapy are urgently needed in order to identify RCC pts who should receive VEGFR inhibitors in the first line.
Herpes Simplex Viruses: New Relationships between Epidemiology and History
Authors: Joseph Caspermeyer
Journal: Molecular Biology and Evolution (2020)

Scientists have revised the dating of viral dispersal from Africa: it did not occur during ancient "Out of Africa" migrations, but rather, more recent events, including the transatlantic slave trade of the eighteenth century. An Italian research team has refined the history and origins of two extremely common pathogens in human populations, herpes simplex virus type 1 and type 2. As many of us may experience, literally on the skin, the common herpes simplex virus type 1 is a primary cause of orofacial lesions. The less prevalent form, herpes simplex virus type 2, is usually responsible for genital herpes. Both viruses can also cause very serious diseases, including nonepidemic encephalitis and neonatal herpes infection. In the latter case, the virus is generally transmitted by the mother during delivery and the consequences can be extremely serious for the infant. To better understand the origins of the virus, the research team has shown that the evolutionary history of these two viruses is different and more complex than previously thought (Forni et al. 2020).
Circulating tumor cell (CTC) genomic signatures of hormone therapy resistance in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Santosh Gupta, Susan Halabi, Gabor Kemeny, Monika Anand, David M. Nanus, Paraskevi Giannakakou, Daniel J. George, Simon Gregory, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2020)

147 Background: Men with CTC AR-V7 + mCRPC have very poor outcomes when treated with enzalutamide/abiraterone. However, many men lack AR-V7. Here, we determined whether baseline or post-treatment DNA alterations in CTCs from AR-V7 negative mCRPC men could provide clinical utility in predicting outcomes with these hormonal therapies. Methods: We analyzed whole-genome copy number alterations (CNA) using array-comparative genomic hybridization (aCGH) in CTCs from 48 men (45 baseline and 28 progression), and whole-exome sequencing (WES) from 11 mCRPC men treated with abi/enza, longitudinally, and focused exclusively on AR-V7 negative men (N = 40) by the Epic-AR-V7 nuclear protein assay, and comparing those men who benefit from therapy vs. who do not. Results: We observed broad heterogeneity of CNAs between patients; common genomic alterations included gain in KDM6A (44%), FOXA1 (44%), MYCN (32%), and AR (38%), and loss in BRCA1 (30%) and PTEN (25%). Men who had the clinical benefit to abi/enza (n = 23, median PFS 10 mo) were more likely to have CTCs with genomic gains of ATM, HSD17B4, or PTEN, and loss of BRAF, ABL1, or NKX3-1. Likewise, men who did not benefit from abi/enza (n = 14, median PFS 2.6 mo) had CTCs with more copy number alterations than men who had clinical benefit (median 19.5 vs. 14, p = 0.01), and were enriched for gain of BRCA2, APC, KDM5D, SPARC, MYCN, AR, and CYP11B1, and loss of PTEN, CHD1, PHLPP1, and NCOR2. After progression on abi/enza, we observed clonal evolution of CTCs harboring gain of ATM, FOXA1, KDM6A, CYP11B1, MYC, APC, and NCOR2, and loss of NCOR1, ERG, and RUNX2. Several COSMIC-validated non-synonymous pathogenic exome mutations were detected in progressed or non-responding patients’ CTC DNA; TP53 (55 vs 27% at baseline), AKAP9 (36 vs 9%), CDK12, KMT2D, and BRAF (each 36 vs 18%), and BRD4 and SPOP (each 18 vs 0%). Conclusions: We demonstrate that specific CTC genomic profiles associated with TP53, PTEN, WNT, DNA repair, epigenetic, and AR signaling, as well as lineage plasticity pathways are associated with worse clinical outcomes in AR-V7 negative men with mCRPC treated with abi/enza. Further mechanistic and validation studies are warranted. Clinical trial information: NCT02269982.
Particulate Matter Inhibits Filaggrin through Aryl Hydrocarbon Receptor, and Shows Synergism with Th2 Cytokines
Authors: Byung Eui Kim, Elena Goleva, Jihyun Kim, Kathryn Vang, Clifton Hall, Kangmo Ahn, Donald Leung
Journal: Journal of Allergy and Clinical Immunology (2020)