tbuckley/cabot-search huggingface dataset:
Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS
Authors: Sarah J. Ross, Alexey S. Revenko, Lyndsey L. Hanson, Rebecca Ellston, Anna Staniszewska, Nicky Whalley, Sanjay K. Pandey, Mitchell Revill, Claire Rooney, Linda K. Buckett, Stephanie K. Klein, Kevin Hudson, Brett P. Monia, Michael Zinda, David C. Blakey, Paul D. Lyne, A. Robert Macleod
Journal: Science Translational Medicine (2017)

Activating mutations in KRAS underlie the pathogenesis of up to 20% of human tumors, and KRAS is one of the most frequently mutated genes in cancer. Developing therapeutics to block KRAS activity has proven difficult, and no direct inhibitor of KRAS function has entered clinical trials. We describe the preclinical evaluation of AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting KRAS mRNA. AZD4785 potently and selectively depleted cellular KRAS mRNA and protein, resulting in inhibition of downstream effector pathways and antiproliferative effects selectively in KRAS mutant cells. AZD4785-mediated depletion of KRAS was not associated with feedback activation of the mitogen-activated protein kinase (MAPK) pathway, which is seen with RAS-MAPK pathway inhibitors. Systemic delivery of AZD4785 to mice bearing KRAS mutant non-small cell lung cancer cell line xenografts or patient-derived xenografts resulted in inhibition of KRAS expression in tumors and antitumor activity. The safety of this approach was demonstrated in mice and monkeys with KRAS ASOs that produced robust target knockdown in a broad set of tissues without any adverse effects. Together, these data suggest that AZD4785 is an attractive therapeutic for the treatment of KRAS-driven human cancers and warrants further development.
Intestine-Specific Homeobox Gene <i>ISX</i> Integrates IL6 Signaling, Tryptophan Catabolism, and Immune Suppression
Authors: Li-Ting Wang, Shyh-Shin Chiou, Chee-Yin Chai, Edward Hsi, Kazunari K. Yokoyama, Shen-Nien Wang, Shau-Ku Huang, Shih-Hsien Hsu
Journal: Cancer Research (2017)

Abstract The intestine-specific homeobox transcription factor intestine-specific homeobox (ISX) is an IL6-inducible proto-oncogene implicated in the development of hepatocellular carcinoma, but its mechanistic contributions to this process are undefined. In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan catabolism, and immune suppression. We found that ISX-mediated IL6-induced expression of the tryptophan catabolic enzymes Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase in hepatocellular carcinoma cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR). Activation of this kynurenine/AHR signaling axis acted through a positive feedback mechanism to increase ISX expression and enhance cellular proliferation and tumorigenic potential. RNAi-mediated attenuation of ISX or AHR reversed these effects. In an IDO1-dependent manner, ectopic expression of ISX induced expression of genes encoding the critical immune modulators CD86 (B7-2) and programmed death ligand-1 (PD-L1), through which ISX conferred a significant suppressive effect on the CD8+ T-cell response. In hepatocellular carcinoma specimens, expression of IDO1, kynurenine, AHR, and PD-L1 correlated negatively with survival. Overall, our results identified a feed-forward mechanism of immune suppression in hepatocellular carcinoma organized by ISX, which involves kynurenine-AHR signaling and PD-L1, offering insights into immune escape by hepatocellular carcinoma, which may improve its therapeutic management. Cancer Res; 77(15); 4065–77. ©2017 AACR.
Increased Idarubicin Dosage during Consolidation Therapy for Adult Acute Myeloid Leukemia Improves Leukemia-Free Survival
Authors: Bradstock Kenneth, Emma Link, Juliana Di Iulio, Jeff Szer, Paula Marlton, Andrew Wei, Arno Enno, Anthony P Schwarer, Ian D. Lewis, James D'Rozario, Luke Coyle, Gavin Cull, Philip Campbell, Michael Francis Leahy, Uwe H Hahn, Paul Cannell, Campbell Tiley, Raymond M. Lowenthal, John Moore, Kimberly Cartwright, Ilona Cunningham, John Taper, Andrew Grigg, Andrew W. Roberts, Warwick John Benson, Mark S Hertzberg, Sandra F. Deveridge, Philip Arthur Rowlings, Anthony K. Mills, Devinder S Gill, Peter G Bardy, Lynda Campbell, John F. Seymour
Journal: Blood (2016)
Longer follow-up on cardiac safety and distant disease free survival of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab in patients with early-stage HER2-positive breast cancer.
Authors: Rui Wang, Anthony Francis Yu, Richard Steingart, Sujata Patil, Jose Baselga, Larry Norton, Cliff Hudis, Chau T. Dang
Journal: Journal of Clinical Oncology (2017)

540 Background: We previously reported the cardiac safety results and distant disease-free survival (DDFS) on a phase 2 trial of dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H) in patients with early stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The incidence of congestive heart failure (CHF) was 1.4% both at a median follow-up of 2 and 7 years. Here, we report updated CHF and DDFS rates with longer follow-up. Methods: Patients were enrolled with HER2 overexpressed (immunohistochemistry 3+) or amplified (fluorescent in situ hybridization ratio &gt; 2.0) disease, regardless of size or nodal status, and baseline left ventricular ejection fraction (LVEF) of &gt; 55%. Patients (pts) received dd AC (60/600 mg/m2) q 2 weeks (w) x 4 →T (175 mg/m2) q 2 w x 4 with H (loading dose 4 mg/kg → 2 mg/kg q w during T → 6 mg/kg q 3 w for rest of 1 year); pegfilgrastim was administered after each chemotherapy cycle. LVEF monitoring with multigated acquisition scan occurred at baseline, months 2 (after AC), 6, 9, and 18 (after therapy completion). Results: From January 2005 to November 2005, 70 pts were enrolled; 2 (3%) and 68 (97%) were treated in neoadjuvant and adjuvant settings, respectively. In 68 pts treated in adjuvant setting, 40 (60%) and 27 (40%) had node-positive and node-negative disease, respectively. The median age was 49 years old (range 27-72); 55 (79%) had hormone-receptor positive disease, 11 (16%) had hypertension, and 21 (30%) had left sided radiation. The median baseline LVEF was 68% [range, 55%-81%]). With a median follow-up of 10.9 yrs, there was no additional CHF event. Therefore, the cumulative incidence of CHF remains to be 1.4% (95% confidence interval [95% CI], 1.36%- 7.7%). The 9 and 10 year DDFS rates were 89% (95% CI, 78%-94%) and 87% (95% CI 75%-93%), respectively. Conclusions: Longer follow-up of this study has demonstrated that ddAC →TH is associated with a low risk of CHF and promising DDFS in patients with early-stage HER2-positive breast cancer.
Updated Results from a Phase 1 Study of TAK-659, an Investigational and Reversible SYK Inhibitor, in Patients (Pts) with Advanced Solid Tumor or Lymphoma Malignancies
Authors: Jason B Kaplan, Leo I Gordon, Jeffrey R Infante, Rakesh Popat, Alessandro Rambaldi, Sumit Madan, Manish R. Patel, Giuseppe Gritti, Chin-Hin Ng, Ian Chau, John A Radford, Jaime Perez de Oteyza, Pier Luigi Zinzani, Stephanie Faucette, Emily Sheldon-Waniga, Miguel Williams, Kate Stumpo, Yaping Shou, Cecilia Carpio, Francesc Bosch
Journal: Blood (2016)
Association Between Mutations in the HFE Gene for Hereditary Haemochromatosis with Iron Stores on Initial Presentation, and Subsequent Venesection Requirements
Authors: F MacCarthy, R O'Hanlon, A Burke, JM Lee
Journal: Endoscopy (2004)

Background: Hereditary Haemochromatosis is an autosomal recessive disorder characterised by increased iron stores and increased deposition of iron in organs such as the liver. It has been shown that patients with Haemochromatosis have mutations in the HFE gene. The most frequently identified mutations are the C282Y and H63D substitution mutations, which are associated with increased iron absorption from the gastrointestinal tract. The standard treatment for this condition is the removal of blood by venesection/phlebotomy. We speculated that different mutation profiles are associated with different degrees of iron overload, and subsequently varying requirements for venesection.
Commentary: View from the frontline of pragmatic trials
Authors: Ashley Woodcock
Journal: BMJ (2017)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Commentary: View from the frontline of pragmatic trials Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Systolic Blood Pressure Trajectory, Frailty, and All-Cause Mortality &gt;80 Years of Age
Authors: Rathi Ravindrarajah, Nisha C. Hazra, Shota Hamada, Judith Charlton, Stephen H.D. Jackson, Alex Dregan, Martin C. Gulliford
Journal: Circulation (2017)

Clinical trials show benefit from lowering systolic blood pressure (SBP) in people ≥80 years of age, but nonrandomized epidemiological studies suggest lower SBP may be associated with higher mortality. This study aimed to evaluate associations of SBP with all-cause mortality by frailty category >80 years of age and to evaluate SBP trajectories before death.A population-based cohort study was conducted using electronic health records of 144 403 participants ≥80 years of age registered with family practices in the United Kingdom from 2001 to 2014. Participants were followed for ≤5 years. Clinical records of SBP were analyzed. Frailty status was classified using the e-Frailty Index into the categories of fit, mild, moderate, and severe. All-cause mortality was evaluated by frailty status and mean SBP in Cox proportional-hazards models. SBP trajectories were evaluated using person months as observations, with mean SBP and antihypertensive treatment status estimated for each person month. Fractional polynomial models were used to estimate SBP trajectories over 5 years before death.During follow-up, 51 808 deaths occurred. Mortality rates increased with frailty level and were greatest at SBP <110 mm Hg. In fit women, mortality was 7.7 per 100 person years at SBP 120 to 139 mm Hg, 15.2 at SBP 110 to 119 mm Hg, and 22.7 at SBP <110 mm Hg. For women with severe frailty, rates were 16.8, 25.2, and 39.6, respectively. SBP trajectories showed an accelerated decline in the last 2 years of life. The relative odds of SBP <120 mm Hg were higher in the last 3 months of life than 5 years previously in both treated (odds ratio, 6.06; 95% confidence interval, 5.40-6.81) and untreated (odds ratio, 6.31; 95% confidence interval, 5.30-7.52) patients. There was no evidence of intensification of antihypertensive therapy in the final 2 years of life.A terminal decline of SBP in the final 2 years of life suggests that nonrandomized epidemiological associations of low SBP with higher mortality may be accounted for by reverse causation if participants with lower blood pressure values are closer, on average, to the end of life.
Investigation of preadmission antibiotic treatment in patients with meningococcal disease
Authors: Ludek Roznovsky, Vera Struncova, Vacla Dostal, Stanislav Plisek, Eduard Kasal, Ivo Burget, Pavel Chalupa, Pavla Krizova, Pavel Dlouhy, Jiri Svejda
Journal: Clinical Microbiology and Infection (2002)
A candidate gene for familial Mediterranean fever
Authors: None The French FMF Consortium, Alain Bernot, Christian Clepet, Corinne Dasilva, Catherine Devaud, Jean-Louis Petit, Christophe Caloustian, Corinne Cruaud, Delphine Samson, Françoise Pulcini, Jean Weissenbach, Roland Heilig, Cécile Notanicola, Cécile Domingo, Michael Rozenbaum, Eldad Benchetrit, Rezzan Topaloglu, Marie Dewalle, Christiane Dross, Philippe Hadjari, Madeleine Dupont, Jacques Demaille, Isabelle Touitou, Nizar Smaoui, Brigitte Nedelec, Jean-Philippe Méry, Habiba Chaabouni, Marc Delpech, Gilles Grateau
Journal: Nature Genetics (1997)
Re-Examining Neutrophil Participation in GN
Authors: Dawn J. Caster, David W. Powell, Irina Miralda, Richard A. Ward, Kenneth R. McLeish
Journal: Journal of the American Society of Nephrology (2017)

Significant advances in understanding the pathogenesis of GN have occurred in recent decades. Among those advances is the finding that both innate and adaptive immune cells contribute to the development of GN. Neutrophils were recognized as key contributors in early animal models of GN, at a time when the prevailing view considered neutrophils to function as nonspecific effector cells that die quickly after performing antimicrobial functions. However, advances over the past two decades have shown that neutrophil functions are more complex and sophisticated. Specifically, research has revealed that neutrophil survival is regulated by the inflammatory milieu and that neutrophils demonstrate plasticity, mediate microbial killing through previously unrecognized mechanisms, demonstrate transcriptional activity leading to the release of cytokines and chemokines, interact with and regulate cells of the innate and adaptive immune systems, and contribute to the resolution of inflammation. Therefore, neutrophil participation in glomerular diseases deserves re-evaluation. In this review, we describe advances in understanding classic neutrophil functions, review the expanded roles of neutrophils in innate and adaptive immune responses, and summarize current knowledge of neutrophil contributions to GN.
Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion
Authors: Levi B. Watkin, Rabinarayan Mishra, Anna Gil, Nuray Aslan, Dario Ghersi, Katherine Luzuriaga, Liisa K. Selin
Journal: Journal of Allergy and Clinical Immunology (2017)
Self-guided online cognitive behavioral strategies for chemotherapy-induced peripheral neuropathy (CIPN): A multicenter, single blind, randomized, wait-list controlled trial.
Authors: Robert Knoerl, James Yang, Debra L. Barton, David A. Williams, Janean Holden, John C. Krauss, Celia Bridges, Ellen M. Lavoie Smith
Journal: Journal of Clinical Oncology (2017)

e21710 Background: Four in 10 individuals receiving neurotoxic chemotherapy develop chronic painful CIPN, symptoms which negatively influence quality of life and physical function, and may require the withdrawal of effective chemotherapy. However, few recommended pharmacological and no effective non-pharmacological treatments for chronic painful CIPN exist. The purpose of the study was to examine the efficacy of an online cognitive behavioral pain management intervention, the PROactive Self-Management Program for Effects of Cancer Treatment ( PROSPECT), to reduce worst pain intensity in individuals with chronic painful CIPN. The secondary outcomes were average pain intensity, non-painful CIPN symptoms, and impaired function. Methods: Sixty patients with chronic painful CIPN were randomized (1:1 ratio) to receive either 8 weeks of PROSPECT or usual care. A 7-day electronic worst CIPN pain intensity diary was completed at the baseline and eight week time points. At the same time points, participants completed electronic standardized measures of functional impairment, non-painful CIPN symptom severity, and average CIPN pain intensity. Mean change scores from baseline and eight week surveys were compared between groups using ANCOVA adjusting for baseline. Results: Individuals who received the PROSPECT intervention had a mean change in worst pain intensity of -0.94 ( SD = 1.36, Range = -3.29 – 1.29). Those in the control group had a mean change score of 0 ( SD = 1.31, Range = -3.43 – 2.86) ( p = 0.046; d = 0.53) ( n = 38). For the secondary outcomes, no significant mean change score differences were found between groups. Conclusions: PROSPECT use significantly improved worst pain intensity, but not secondary outcomes, in individuals with chronic painful CIPN. A larger study testing PROSPECT is needed to determine if improvements in worst pain intensity may be sustained, to evaluate the effect of the intervention on the secondary outcomes, and to identify mediators of pain-related improvement. If shown to be efficacious with further testing, PROSPECT may be added to pharmacological modalities for the treatment of chronic painful CIPN. Clinical trial information: NCT02760654.
The somatic mutation landscape of premalignant colorectal adenoma
Authors: Shu-Hong Lin, Gottumukkala S Raju, Chad Huff, Yuanqing Ye, Jian Gu, Jiun-Sheng Chen, Michelle A T Hildebrandt, Han Liang, David G Menter, Jeffery Morris, Ernest Hawk, John R Stroehlein, Andrew Futreal, Scott Kopetz, Lopa Mishra, Xifeng Wu
Journal: Gut (2017)

Objective There are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers of progression from colorectal adenoma to adenocarcinoma. Design Whole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC. Results Similar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941. Conclusion The findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC.
Abstract 50: GATA4-Dependent Control of Myocyte Protein Quality Mediated by HSPB7
Authors: Emily J Mercer, Todd Evans
Journal: Circulation Research (2015)

The transcription factor GATA4 plays essential roles in heart development, including regulation of cardiomyocyte stress response. GATA4 depletion leads to defective cardiogenesis while GATA4 overexpression is protective in stress models including myocardial ischemia and cardiotoxin administration. However, the molecular basis for GATA4 function remains poorly understood. We discovered that expression of small heat shock protein beta 7 (HSPB7) is regulated by GATA4 and that HSPB7 depletion causes defects in cardiomorphogenesis. The goal of our study is to determine the cellular and molecular mechanism of action of HSPB7 in cardiomyogenesis. Through proteomic mass spectrometry and co-immunoprecipitation, we identified Filamin C (FLNC), a large sarcomeric protein, as an HSPB7 binding partner. FLNC mutations lead to pathological aggregate formation and progressive myopathy. Previous work suggests HSPB7 may prevent damaged protein aggregation through autophagic pathways, and our studies in zebrafish embryos suggest HSPB7 depletion alters the morphology and cytoskeletal architecture of ventricular cardiomyocytes, in particular the trabeculae. We hypothesize that HSPB7 facilitates myocyte function by processing damaged FLNC to prevent aggregation. Preliminary data suggest that BAG3 is also a part of this chaperone complex, linking HSPB7 to the process of Chaperone Assisted Selective Autophagy. Interestingly, disturbing autophagic pathways in the chick embryo precipitates dextrocardia, a phenotype observed in HPSB7 morphant embryos. We also generated a spectrum of defined HSPB7 mutant alleles using TALEN technology. Four such alleles have been bred to homozygosity including a suspected N-terminal truncation that deletes a putative regulatory polyserine stretch. Although homozygous mutants do not exhibit an overt cardiac phenotype, we hypothesize that loss of this polyserine domain may result in a hypomorphic HSPB7 protein. Exposure of mutant embryos to various stressors, including increased temperature (32°C) and the autophagy inducer rapamycin (1μM), led to an increase in phenotypes we have observed in HSPB7 morphants, including dextrocardia and the incidence of defects in cardiac morphology.
Біоімпедансметрія в оцінці нутритивного статусу хворих на хронічні запальні захворювання кишечника
Authors: Yu.M. Stepanov, T.Y. Boiko, O.V. Sorochan, M.V. Stoikevych, A.S. Shkaredna
Journal: GASTROENTEROLOGY (2020)

Стаття присвячена вивченню нутритивного статусу хворих на хронічні запальні захворювання кишечника (ХЗЗК) за допомогою біоімпедансметрії. Обстежено 40 хворих на ХЗЗК. Встановлено високу частоту відхилень масової частки жиру в організмі (87,5 %) з переважанням нутритивної недостатності (65,0 %), що асоціювалася зі зниженням адаптаційних можливостей організму та тяжким перебігом захворювання. Для 70,0 % обстежених хворих був характерний перерозподіл водних секторів організму за рахунок збільшення позаклітинної рідини та зменшення внутрішньоклітинної рідини, який був більш вираженим у пацієнтів із підвищеним нутритивним статусом порівняно з хворими з нутритивною недостатністю. Більш виражені зміни компонентного складу тіла були характерні для хворих на хворобу Крона.
CRISPR Epigenome Editing of AKAP150 in DRG Neurons Abolishes Degenerative IVD-Induced Neuronal Activation
Authors: Joshua D. Stover, Niloofar Farhang, Kristofer C. Berrett, Jason Gertz, Brandon Lawrence, Robby D. Bowles
Journal: Molecular Therapy (2017)

Back pain is a major contributor to disability and has significant socioeconomic impacts worldwide. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to back pain, but a better understanding of the interactions between the degenerative IVD and nociceptive neurons innervating the disc and treatment strategies that directly target these interactions is needed to improve our understanding and treatment of back pain. We investigated degenerative IVD-induced changes to dorsal root ganglion (DRG) neuron activity and utilized CRISPR epigenome editing as a neuromodulation strategy. By exposing DRG neurons to degenerative IVD-conditioned media under both normal and pathological IVD pH levels, we demonstrate that degenerative IVDs trigger interleukin (IL)-6-induced increases in neuron activity to thermal stimuli, which is directly mediated by AKAP and enhanced by acidic pH. Utilizing this novel information on AKAP-mediated increases in nociceptive neuron activity, we developed lentiviral CRISPR epigenome editing vectors that modulate endogenous expression of AKAP150 by targeted promoter histone methylation. When delivered to DRG neurons, these epigenome-modifying vectors abolished degenerative IVD-induced DRG-elevated neuron activity while preserving non-pathologic neuron activity. This work elucidates the potential for CRISPR epigenome editing as a targeted gene-based pain neuromodulation strategy.
Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non–Small Cell Lung Cancer: NRG Oncology RTOG 0839
Authors: Martin J. Edelman, Chen Hu, Quynh-Thu Le, Jessica S. Donington, Warren D. D’Souza, Adam P. Dicker, Billy W. Loo, Elizabeth M. Gore, Gregory M.M. Videtic, Nathaniel R. Evans, Joseph W. Leach, Maximilian Diehn, Steven J. Feigenberg, Yuhchyau Chen, Rebecca Paulus, Jeffrey D. Bradley
Journal: Journal of Thoracic Oncology (2017)